Prevention of loss and restoration of bone mass by certain prostaglandin agonists

ABSTRACT

Prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority of U.S. application Ser. No.09/331,081, filed Jun. 11, 1999, which is a 371 of PCT/IB97/01417 filedNov. 10, 1997, which claims priority of U.S. Provisional Application No.60/033,451, filed Dec. 20, 1996.

BACKGROUND OF INVENTION

[0002] This invention relates to prostaglandin agonists, pharmaceuticalcompositions containing such agonists and the use of such agonists toprevent bone loss or restore or augment bone mass including thetreatment of conditions which present with low bone mass in mammals,including humans.

[0003] Osteoporosis is a systemic skeletal disease, characterized by lowbone mass and deterioration of bone tissue, with a consequent increasein bone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being physically impaired.

[0004] The elderly are at greatest risk of osteoporosis, and the problemis therefore predicted to increase significantly with the aging of thepopulation. Worldwide fracture incidence is forecasted to increasethree-fold over the next 60 years, and one study estimated that therewill be 4.5 million hip fractures worldwide in 2050.

[0005] Women are at greater risk of osteoporosis than men. Womenexperience a sharp acceleration of bone loss during the five yearsfollowing menopause. Other factors that increase the risk includesmoking, alcohol abuse, a sedentary lifestyle and low calcium intake.

[0006] There are currently two main types of pharmaceutical therapy forthe treatment of osteoporosis. The first is the use of anti-resorptivecompounds to reduce the resorption of bone tissue. alternative therapiesfor osteoporosis that have the desirable effect on serum LDL but do notcause undesirable effects.

[0007] A second type of pharmaceutical therapy for the treatment ofosteoporosis is the use of anabolic agents to promote bone formation andincrease bone mass. This class of agents is expected to restore bone tothe established osteoporotic skeleton.

[0008] U.S. Pat. No. 4,112,236 discloses certain interphenylene8-aza-9-dioxothia-11,12-secoprostaglandins for the treatment of patientswith renal impairment.

[0009] Certain prostagladin agonists are disclosed in GB 1478281,GB1479156 and U.S. Pat. Nos. 4,175,203, 4,055,596, 4,175,203, 3,987,091and 3,991,106 as being useful as, for example, renal vasodilators.

[0010] U.S. Pat. No. 4,033,996 discloses certain 8-aza-9-oxo(anddioxo)-thia-11,12-secoprostaglandins which are useful as renalvasodilators, for the prevention of thrombus formation, to induce growthhormone release, and as regulators of the immune response.

[0011] French patent no. 897,566 discloses certain amino acidderivatives for the treatment of neurological, mental or cardiovasculardisease.

[0012] J. Org. Chem. 26; 1961; 1437 disclosesN-acetyl-N-benzyl-p-aminophenylmercaptoacetic acid.

[0013] In addition to osteoporosis, approximately, 20-25 million womenand an increasing number of men have detectable vertebral fractures as aconsequence of reduced bone mass, with an additional 250,000 hipfractures reported yearly in America alone. The latter case isassociated with a 12% mortality rate within the first two years and witha 30% rate of patients requiring nursing home care after the fracture.While this is already significant, the economic and medical consequencesof convalescence due to slow or imperfect healing of these bonefractures is expected to increase, due to the aging of the generalpopulation. While there are several promising therapies(bis-phosphonates, etc.) in development to prevent bone loss with ageand thus reduce the probability of incurring debilitating fractures,these therapies are not indicated for restoration of bone mass once thefracture has occurred.

[0014] Estrogens have been shown (Bolander et al., 38th Annual MeetingOrthopedic Research Society, 1992) to improve the quality of the healingof appendicular fractures. Therefore, estrogen replacement therapy mightappear to be a method for the treatment of fracture repair. However,patient compliance with estrogen therapy is relatively poor due to itsside effects, including the resumption of menses, mastodynia, anincreased risk of uterine cancer, an increased perceived risk of breastcancer, and the concomitant use of progestins. In addition, men arelikely to object to the use of estrogen treatment. Clearly the needexists for a therapy which would be beneficial to patients who havesuffered debilitating bone fractures or who have low bone mass and whichwould increase patient compliance.

[0015] Although there are a variety of osteoporosis therapies there is acontinuing need and a continuing search in this field of art foralternative osteoporosis therapies. In addition, there is a need forbone fracture healing therapies.

SUMMARY OF THE INVENTION

[0016] This invention is directed to a compound of Formula I

[0017] or a pharmaceutically-acceptable salt or prodrug thereof whereineither (i):

[0018] B is N;

[0019] A is (C₁-C₆)alkylsulfonyl, (C₃-C₇)cycloalkylsulfonyl,(C₃-C₇)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di- or tri-substituted on carbon independently with hydroxy,(C₁-C₄)alkyl or halo;

[0020] Q is

[0021] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0022] —(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0023] —X—(C₁-C₅)alkylene-,

[0024] —(C₁-C₅)alkylene-X-,

[0025] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0026] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,

[0027] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,

[0028] —(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the twooccurrences of W are independent of each other,

[0029] —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

[0030] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,

[0031] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,

[0032] —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

[0033] —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-;

[0034] W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N—(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

[0035] X is a five or six membered aromatic ring optionally having oneor two heteroatoms selected independently from oxygen, nitrogen, andsulfur; said ring optionally mono-, or di-substituted independently withhalo, (C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy,difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

[0036] Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl,(C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;

[0037] K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene oroxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionally mono-unsaturated andwherein K is optionally mono-, di- or tri-substituted independently withfluoro, methyl or chloro;

[0038] M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹and Ar² are each independently a partially saturated, fully saturated orfully unsaturated five to eight membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or, a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated five or six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0039] said Ar, Ar¹ and Ar² moieties optionally substituted, on one ringif the moiety is monocyclic, or one or both rings if the moiety isbicyclic, on carbon with up to three substituents independently selectedfrom R¹, R² and R³ wherein R¹, R² and R³ are hydroxy, nitro, halo,(C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl;

[0040] R¹, R² and R³ are optionally mono-, di- or tri-substituted oncarbon independently with halo or hydroxy; and

[0041] V is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro

[0042] with the proviso that when K is (C₂-C₄)alkylene and M is Ar andAr is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-ylthen said (C₅-C₈)cycloalkyl substituents are not substituted at the oneposition with hydroxy;

[0043] or (ii):

[0044] B is N;

[0045] A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted independently oncarbon with hydroxy or halo;

[0046] Q is

[0047] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0048] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0049] —X—(C₂-C₅)alkylene-,

[0050] —(C₁-C₅)alkylene-X—,

[0051] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0052] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,

[0053] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,

[0054] —(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the twooccurrences of W are independent of each other,

[0055] —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

[0056] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,

[0057] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,

[0058] —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

[0059] —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-;

[0060] W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N—(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

[0061] X is a five or six membered aromatic ring optionally having oneor two heteroatoms independently selected from oxygen, nitrogen, andsulfur; said ring optionally mono-, or di-substituted independently withhalo, (C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy,difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

[0062] Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl,(C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;

[0063] K is (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene,said (C₁-C₈)alkylene optionally mono-unsaturated and wherein K isoptionally mono-, di- or tri-substituted independently with fluoro,methyl or chloro;

[0064] M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹and Ar² are each independently a partially saturated, fully saturated orfully unsaturated five to eight membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or, a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated five or six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0065] said Ar, Ar¹ and Ar² moieties optionally substituted, on one ringif the moiety is monocyclic, or one or both rings if the moiety isbicyclic, on carbon with up to three substituents independently selectedfrom R¹, R² and R³ wherein R¹, R² and R³ are H, hydroxy, nitro, halo,(C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl;

[0066] R¹, R² and R³ are optionally mono-, di- or tri-substituted oncarbon independently with halo or hydroxy; and

[0067] V is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro

[0068] with the proviso that when K is (C₂-C₄)alkylene and M is Ar andAr is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl thensaid (C₅-C₈)cycloalkyl substituents are not substituted at the oneposition with hydroxy

[0069] and with the proviso that6-[(3-Phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and itsethyl ester are not included

[0070] or (iii):

[0071] B is C(H);

[0072] A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted on carbonindependently with hydroxy or halo;

[0073] Q is

[0074] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0075] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0076] —X—(C₁-C₅)alkylene-,

[0077] —(C₁-C₅)alkylene-X—,

[0078] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0079] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,

[0080] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,

[0081] —(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the twooccurrences of W are independent of each other,

[0082] —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

[0083] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,

[0084] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,

[0085] —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

[0086] —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-;

[0087] W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N—(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

[0088] X is a five or six membered aromatic ring optionally having oneor two heteroatoms selected independently from oxygen, nitrogen andsulfur; said ring optionally mono-, or di-substituted independently withhalo, (C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy,difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

[0089] Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl,(C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;

[0090] K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene,(C₄-C₇)cycloalkyl(C₁-C₆)alkylene or oxy(C₁-C₄)alkylene, said(C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionallymono-, di- or tri-substituted independently with fluoro, methyl orchloro;

[0091] M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹and Ar² are each independently a partially saturated, fully saturated orfully unsaturated five to eight membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or, a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated five or six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0092] said Ar, Ar¹ and Ar² moieties optionally substituted, on one ringif the moiety is monocyclic, or one or both rings if the moiety isbicyclic, on carbon with up to three substituents independently selectedfrom R¹, R² and R³ wherein R¹, R² and R³ are H, hydroxy, nitro, halo,(C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl;

[0093] R¹, R² and R³ are optionally mono-, di- or tri-substitutedindependently on carbon with halo or hydroxy; and

[0094] V is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro

[0095] with the proviso that when K is (C₂-C₄)alkylene and M is Ar andAr is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-ylthen said (C₅-C₈)cycloalkyl substituents are not substituted at the oneposition with hydroxy.

[0096] A preferred group of compounds, designated the A Group, containsthose compounds having the Formula I as shown above wherein

[0097] B is N;

[0098] A is (C₁-C₆)alkylsulfonyl, (C₃-C₆)cycloalkylsulfonyl or(C₃-C₆)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di-, or tri-substituted on carbon with fluoro;

[0099] X is phenyl, thienyl, or thiazolyl said phenyl, thienyl orthiazolyl optionally mono- or di-substituted independently with fluoro,chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0100] W is oxy, thio or sulfonyl;

[0101] Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

[0102] K is methylene or ethylene;

[0103] Ar, Ar¹ and Ar² are each independently (C₅-C₇)cycloalkyl, phenyl,thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl,isoxazolyl, pyrazinyl or pyrazolyl;

[0104] R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-,di- or tri-substituted independently with hydroxy, fluoro or chloro; and

[0105] R² and R³ are chloro, fluoro, methyl, methoxy, difluoromethoxy,trifluoromethoxy or trifluoromethyl.

[0106] A group of compounds which is preferred among the A Group ofcompounds designated the B Group, contains those compounds wherein

[0107] A is (C₁-C₃)alkylsulfonyl;

[0108] Q is

[0109] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0110] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0111] —X—(C₂-C₅)alkylene-,

[0112] —(C₁-C₅)alkylene-X—,

[0113] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0114] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0115] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0116] M is —Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are eachindependently phenyl, pyridyl or thienyl;

[0117] V is a bond or (C₁-C₂)alkylene;

[0118] R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said(C₁-C₄)alkyl and (C₁-C₄)alkoxy optionally mono-, di- or tri-substitutedindependently with hydroxy or fluoro; and

[0119] R² and R³ are each independently chloro or fluoro.

[0120] Especially preferred compounds within the B Group of compoundsare

[0121]7-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid,

[0122]7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoicacid, and

[0123]7-[(2′-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid.

[0124] Especially preferred compounds within the B Group of compoundsare compounds wherein

[0125] a. A is methylsulfonyl;

[0126] Q is n-hexylene;

[0127] Z is carboxyl;

[0128] K is methylene; and

[0129] M is 4-(2-hydroxymethylphenyl)phenyl;

[0130] b. A is methylsulfonyl;

[0131] Q is n-hexylene;

[0132] Z is carboxyl;

[0133] K is methylene; and

[0134] M is 4-(3-hydroxymethylthien-2-yl)phenyl; and

[0135] c. A is methylsulfonyl;

[0136] Q is n-hexylene;

[0137] Z is carboxyl;

[0138] K is methylene; and

[0139] M is 4-(2-chlorophenyl)phenyl.

[0140] A preferred group of compounds, designated the C Group, containsthose compounds having the Formula I as shown above wherein

[0141] B is N;

[0142] A is (C₁-C₆)alkylsulfonyl, (C₃-C₆)cycloalkylsulfonyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkylsulfonyl;

[0143] X is phenyl, thienyl, or thiazolyl said phenyl, thienyl orthiazolyl optionally mono- or di-substituted independently with fluoro,chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy;

[0144] W is oxy, thio or sulfonyl;

[0145] Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl

[0146] K is (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with methyl, fluoro or chloro;

[0147] M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl,oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl,indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl,benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl,cyclopentyl, cyclobutyl, cycloheptyl or chromanyl;

[0148] R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and

[0149] R² and R³ are each independently hydroxy, halo, trifluoromethyl,(C₁-C₇)alkyl, (C₁C₄)alkoxy, (C₁-C₅)alkanoyl, cyano, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl, difluoromethoxy, trifluoromethoxyor carbamoyl.

[0150] It is especially preferred for Group C compounds that K is notoptionally mono-, di- or tri-substituted independently with methyl,fluoro or chloro.

[0151] A group of compounds which is preferred among the C Group ofcompounds, designated the D Group, contains those compounds wherein

[0152] K is methylene;

[0153] A is (C₁-C₃)alkylsulfonyl;

[0154] M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl,oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substitutedwith at least R¹;

[0155] R¹ is (C₁-C₇)alkyl or (C₁-C₅)alkoxy, said (C₁-C₇)alkyl or(C₁-C₅)alkoxy optionally mono-, di- or tri-substituted independentlywith hydroxy or fluoro; and

[0156] R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.

[0157] Especially preferred among the D Group of compounds are

[0158] 7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoicacid,

[0159] 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid,

[0160]7-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoicacid and

[0161](3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid.

[0162] A group of compounds which is preferred among the D Group ofcompounds, designated the E Group, contains those compounds wherein

[0163] Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and

[0164] W is oxy.

[0165] A group of compounds which is preferred among the D Group ofcompounds, designated the F Group, contains those compounds wherein

[0166] Q is —(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionallysubstituted with from one to four fluorines.

[0167] Especially preferred compounds among the F Group of compounds arecompounds wherein

[0168] a. A is methylsulfonyl;

[0169] Q is n-hexylene;

[0170] Z is carboxyl;

[0171] K is methylene; and

[0172] M is 4-(1-hydroxy-n-hexylene-1-yl)phenyl;

[0173] b. A is methylsulfonyl;

[0174] Q is n-hexylene;

[0175] Z is carboxyl;

[0176] K is methylene; and

[0177] M is 4-(n-butylene-1-yl)phenyl; and

[0178] c. A is methylsulfonyl;

[0179] Q is n-hexylene;

[0180] Z is carboxyl;

[0181] K is methylene; and

[0182] M is 5-(1-hydroxy-n-hexylene-1-yl)thien-2-yl.

[0183] A group of compounds which is preferred among the D Group ofcompounds, designated the G Group, contains those compounds wherein

[0184] Q is —X—(C₁-C₅)alkylene-; and

[0185] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0186] A group of compounds which is preferred among the D Group ofcompounds, designated the H Group, contains those compounds wherein

[0187] Q is —(C₁-C₅)alkylene-X—; and

[0188] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0189] A group of compounds which is preferred among the D Group ofcompounds, designated the I Group, contains those compounds wherein

[0190] Q is —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and

[0191] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0192] An especially preferred compound within the I Group of compoundsis a compound wherein

[0193] A is methylsulfonyl;

[0194] Q is 3-methylenephenylmethyl;

[0195] Z is carboxyl;

[0196] K is methylene; and

[0197] M is 4-(n-butylene-1-yl)phenyl.

[0198] A group of compounds which is preferred among the D Group ofcompounds, designated the J Group, contains those compounds wherein

[0199] Q is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-;

[0200] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0201] W is oxy.

[0202] A group of compounds which is preferred among the D Group ofcompounds, designated the K Group, contains those compounds wherein

[0203] Q is —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0204] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0205] W is oxy.

[0206] A group of compounds which is preferred among the D Group ofcompounds, designated the L Group, contains those compounds wherein

[0207] Q is —(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-;

[0208] W is oxy; and

[0209] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0210] A group of compounds which is preferred among the D Group ofcompounds, designated the M Group, contains those compounds wherein

[0211] Q is —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

[0212] M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

[0213] A group of compounds which is preferred among the D Group ofcompounds, designated the N Group, contains those compounds wherein

[0214] Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and

[0215] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0216] A group of compounds which is preferred among the D Group ofcompounds, designated the O Group, contains those compounds wherein

[0217] Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-;

[0218] W is oxy; and

[0219] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0220] A group of compounds which is preferred among the D Group ofcompounds, designated the P Group, contains those compounds wherein

[0221] Q is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

[0222] A group of compounds which is preferred among the D Group ofcompounds designated the Q Group, contains those compounds wherein

[0223] Q is —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and

[0224] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0225] A group of compounds which is preferred among the C Group ofcompounds designated the R Group, contains those compounds wherein

[0226] A is (C₁-C₃)alkylsulfonyl;

[0227] K is (C₁-C₈)alkylene;

[0228] —Ar is phenyl, thiazolyl, pyridyl, thienyl, benzofuranyl,benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxine,2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentylor cyclohexyl; and

[0229] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or(C₁-C₇)alkyl.

[0230] Preferred compounds among the R Group are

[0231] 7-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid,

[0232]7-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid and

[0233]5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid.

[0234] A group of compounds which is preferred among the R Group ofcompounds, designated the S Group, contains those compounds wherein

[0235] Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and

[0236] W is oxy.

[0237] A group of compounds which is preferred among the R Group ofcompounds, designated the T Group, contains those compounds wherein

[0238] Q is —(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionallysubstituted with from one to four fluorines.

[0239] Especially preferred compounds among the T Group are compoundswherein

[0240] a. A is methylsulfonyl;

[0241] Q is n-hexylene;

[0242] Z is carboxyl;

[0243] K is propylene; and

[0244] M is 3-chlorophenyl; and

[0245] b. A is methylsulfonyl;

[0246] Q is n-hexylene;

[0247] Z is carboxyl;

[0248] K is propylene; and

[0249] M is 3,5-dichlorophenyl.

[0250] A group of compounds which is preferred among the R Group ofcompounds, designated the U Group, contains those compounds wherein

[0251] Q is —X—(C₁-C₅)alkylene-; and

[0252] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0253] A group of compounds which is preferred among the R Group ofcompounds, designated the V Group, contains those compounds wherein

[0254] Q is —(C₁-C₅)alkylene-X—; and

[0255] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0256] An especially preferred compound among the V group is a compoundwherein

[0257] A is methylsulfonyl;

[0258] Q—Z is 3-(2-carboxylthien-5-yl)-n-propylene

[0259] K is propylene; and

[0260] M is 3-chlorophenyl.

[0261] A group of compounds which is preferred among the R Group ofcompounds, designated the W Group, contains those compounds wherein

[0262] Q is —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and

[0263] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0264] A group of compounds which is preferred among the R Group ofcompounds, designated the X Group, contains those compounds wherein

[0265] Q is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-;

[0266] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0267] W is oxy.

[0268] A group of compounds which is preferred among the R Group ofcompounds, designated the Y Group, contains those compounds wherein

[0269] Q is —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0270] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0271] W is oxy.

[0272] A group of compounds which is preferred among the R Group ofcompounds, designated the Z Group, contains those compounds wherein

[0273] Q is —(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-;

[0274] W is oxy; and

[0275] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0276] A group of compounds which is preferred among the R Group ofcompounds, designated the A1 Group, contains those compounds wherein

[0277] Q is —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

[0278] M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

[0279] A group of compounds which is preferred among the R Group ofcompounds, designated the B1 Group, contains those compounds wherein

[0280] Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and

[0281] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0282] A group of compounds which is preferred among the R Group ofcompounds, designated the C1 Group, contains those compounds wherein

[0283] Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-;

[0284] W is oxy; and

[0285] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0286] A group of compounds which is preferred among the R Group ofcompounds, designated the D1 Group, contains those compounds wherein

[0287] Q is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

[0288] A group of compounds which is preferred among the R Group ofcompounds, designated the E1 Group, contains those compounds wherein

[0289] Q is —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and

[0290] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0291] A group of compounds which is preferred among the C Group ofcompounds, designated the F1 Group, contains those compounds wherein

[0292] A is (C₁-C₃)alkylsulfonyl;

[0293] K is oxy(C₁-C₄)alkylene;

[0294] —Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl,cyclopentyl or cyclohexyl; and

[0295] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or(C₁-C₇)alkyl.

[0296] Especially preferred compounds within the F1 Group are

[0297]7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid,

[0298]5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid and

[0299]N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.

[0300] A group of compounds which is preferred among the F1 Group ofcompounds, designated the G1 group, contains those compounds wherein

[0301] Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and

[0302] W is oxy.

[0303] A group of compounds which is preferred among the F1 Group ofcompounds, designated the H1 Group, contains those compounds wherein

[0304] Q is —(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionallysubstituted with from one to four fluorines.

[0305] An especially preferred compound among the H1 group of compoundsis a compound wherein

[0306] A is methylsulfonyl;

[0307] Q is n-hexylene;

[0308] Z is carboxyl;

[0309] K is oxyethylene; and

[0310] M is 3,5-dichlorophenyl.

[0311] A group of compounds which is preferred among the F1 Group ofcompounds, designated the I1 Group, contains those compounds wherein

[0312] Q is —X—(C₁-C₅)alkylene-; and

[0313] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0314] A group of compounds which is preferred among the F1 Group ofcompounds, designated the J1 Group, contains those compounds wherein

[0315] Q is —(C₁-C₅)alkylene-X—; and

[0316] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0317] An especially preferred compound among the J1 group is a compoundwherein

[0318] A is methylsulfonyl;

[0319] Q—Z is 3-(2-carboxylthien-5-yl)-n-propylene;

[0320] K is oxyethylene; and

[0321] M is 3,5-dichlorophenyl.

[0322] A group of compounds which is preferred among the F1 Group ofcompounds, designated the K1 Group, contains those compounds wherein

[0323] Q is —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and

[0324] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0325] A group of compounds which is preferred among the F1 Group ofcompounds, designated the L1 Group, contains those compounds wherein

[0326] Q is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-;

[0327] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0328] W is oxy.

[0329] A group of compounds which is preferred among the F1 Group ofcompounds, designated the M1 Group, contains those compounds wherein

[0330] Q is —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0331] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0332] W is oxy.

[0333] A group of compounds which is preferred among the F1 Group ofcompounds, designated the N1 Group, contains those compounds wherein

[0334] Q is —(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-;

[0335] W is oxy; and

[0336] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0337] A group of compounds which is preferred among the F1 Group ofcompounds, designated the O1 Group, contains those compounds wherein

[0338] Q is —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

[0339] M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

[0340] A group of compounds which is preferred among the F1 Group ofcompounds, designated the P1 Group, contains those compounds wherein

[0341] Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and

[0342] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0343] A group of compounds which is preferred among the F1 Group ofcompounds, designated the Q1 Group, contains those compounds wherein

[0344] Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-;

[0345] W is oxy; and

[0346] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0347] A group of compounds which is preferred among the F1 Group ofcompounds, designated the R1 Group, contains those compounds wherein

[0348] Q is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

[0349] A group of compounds which is preferred among the F1 Group ofcompounds, designated the S1 Group, contains those compounds wherein

[0350] Q is —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and

[0351] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0352] A group of compounds which is preferred among the C1 Group ofcompounds, designated the T1 Group, contains those compounds wherein

[0353] A is (C₁-C₃)alkylsulfonyl;

[0354] K is (C₃-C₈)alkylene, said (C₃-C₈)alkylene beingmono-unsaturated;

[0355] —Ar is phenyl, thienyl, thiazolyl, pyridyl, cyclopentyl orcyclohexyl; and

[0356] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or(C₁-C₇)alkyl.

[0357] Especially preferred compounds among the T1 Group are

[0358]Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-aceticacid,

[0359]Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazolyl-5-yl)-hexyl]-methanesulfonamide,

[0360]Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid and

[0361]Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid.

[0362] A group of compounds which is preferred among the T1 Group ofcompounds, designated the U1 Group, contains those compounds wherein

[0363] Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and

[0364] W is oxy.

[0365] An especially preferred compound among the U1 group is a compoundwherein

[0366] A is methylsulfonyl;

[0367] Q is methyloxy-n-butylene;

[0368] Z is carboxyl;

[0369] K is trans-2-n-propenylene; and

[0370] M is 3,5-dichlorophenyl.

[0371] A group of compounds which is preferred among the T1 Group ofcompounds, designated the V1 Group, contains those compounds wherein

[0372] Q is —(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionallysubstituted with from one to four fluorines.

[0373] A preferred compound among the V1 group of compound is a compoundwherein

[0374] A is methylsulfonyl;

[0375] Q is n-hexylene;

[0376] Z is 5-(1H-tetrazolyl);

[0377] K is trans-2-n-propeneylene; and

[0378] M is 3,5-dichlorophenyl.

[0379] A group of compounds which is preferred among the T1 Group ofcompounds, designated the W1 Group, contains those compounds wherein

[0380] Q is —X—(C₁-C₅)alkylene-; and

[0381] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0382] A group of compounds which is preferred among the T1 Group ofcompounds, designated the X1 Group, contains those compounds wherein

[0383] Q is —(C₁-C₅)alkylene-X—; and

[0384] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0385] A preferred compound among the X1 Group is a compound wherein

[0386] A is methylsulfonyl;

[0387] Q—Z is 3-(2-carboxylthien-5-yl)-n-propylene;

[0388] K is trans-2-n-propeneylene; and

[0389] M is 3,5-dichlorophenyl.

[0390] A group of compounds which is preferred among the T1 Group ofcompounds, designated the Y1 Group, contains those compounds wherein

[0391] Q is —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and

[0392] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0393] A group of compounds which is preferred among the T1 Group ofcompounds, designated the Z1 Group, contains those compounds wherein

[0394] Q is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-;

[0395] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0396] W is oxy.

[0397] A group of compounds which is preferred among the T1 Group ofcompounds, designated the A2 Group, contains those compounds wherein

[0398] Q is —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0399] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and

[0400] W is oxy.

[0401] A group of compounds which is preferred among the T1 Group ofcompounds, designated the B2 Group, contains those compounds wherein

[0402] Q is —(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-;

[0403] W is oxy; and

[0404] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0405] A group of compounds which is preferred among the T1 Group ofcompounds, designated the C2 Group, contains those compounds wherein

[0406] Q is —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and

[0407] M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.

[0408] A group of compounds which is preferred among the T1 Group ofcompounds, designated the D2 Group, contains those compounds wherein

[0409] Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and

[0410] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0411] A group of compounds which is preferred among the T1 Group ofcompounds, designated the E2 Group, contains those compounds wherein

[0412] Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-;

[0413] W is oxy; and

[0414] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0415] A group of compounds which is preferred among the T1 Group ofcompounds, designated the F2 Group, contains those compounds wherein

[0416] Q is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.

[0417] A group of compounds which is preferred among the T1 Group ofcompounds, designated the G2 Group, contains those compounds wherein

[0418] Q is —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and

[0419] X is thienyl or phenyl; said phenyl and thienyl optionally mono-or di-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.

[0420] A preferred group of compounds, designated the H2 Group, containsthose compounds having the Formula I as shown above wherein

[0421] B is N;

[0422] A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted on carbonindependently with hydroxy or halo;

[0423] X is phenyl, thienyl, or thiazolyl said phenyl, thienyl orthiazolyl optionally mono- or di-substituted independently with fluoro,chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0424] W is oxy, thio or sulfonyl;

[0425] Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

[0426] K is (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with methyl, fluoro or chloro;

[0427] Ar is (C₅-C₇)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl,oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl,indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl,benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl,cyclohexyl, cyclopentyl, or chromanyl;

[0428] Ar¹ and Ar² are each independently (C₅-C₇)cycloalkyl, phenyl,thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl,isoxazolyl, pyrazinyl or pyrazolyl;

[0429] R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and

[0430] R² and R³ are each independently hydroxy, halo, difluoromethoxy,trifluoromethoxy, trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy,(C₁-C₅)alkanoyl, cyano, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl or carbamoyl.

[0431] It is especially preferred for the H2 Group that K is notoptionally mono-, di- or tri-substituted independently with methyl,fluoro or chloro.

[0432] A group of compounds which is preferred among the H2 Group ofcompounds, designated the I2 Group, contains those compounds wherein

[0433] A is (C₁-C₆)alkanoyl, said (C₁-C₆)alkanoyl optionally mono-, di-or tri-substituted on carbon independently with halo;

[0434] Q is

[0435] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0436] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0437] —X—(C₂-C₅)alkylene-,

[0438] —(C₁-C₅)alkylene-X—,

[0439] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0440] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0441] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,

[0442] K is methylene or ethylene;

[0443] M is —Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are eachindependently phenyl, pyridyl or thienyl;

[0444] V is a bond or (C₁-C₂)alkylene;

[0445] R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₆)alkoxy, said(C₁-C₄)alkyl and (C₁-C₆)alkoxy optionally mono-, di-or tri-substitutedindependently with hydroxy or fluoro; and

[0446] R² and R³ are each independently chloro or fluoro.

[0447] A group of compounds which is preferred among the H2 Group ofcompounds, designated the J2 Group, contains those compounds wherein

[0448] A is (C₁-C₆)alkanoyl said (C₁-C₆)alkanoyl optionally mono-, di-or tri-substituted independently on carbon with hydroxy or halo;

[0449] K is methylene;

[0450] Q is

[0451] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0452] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0453] —X—(C₂-C₅)alkylene-,

[0454] —(C₁-C₅)alkylene-X—,

[0455] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0456] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0457] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0458] M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl,oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substitutedwith at least R¹;

[0459] R¹ is (C₁-C₇)alkyl or (C₁-C₅)alkoxy, said (C₁-C₇)alkyl or(C₁-C₅)alkoxy optionally mono-, di- or tri-substituted independentlywith hydroxy or fluoro; and

[0460] R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.

[0461] A group of compounds which is preferred among the H2 Group ofcompounds, designated the K2 Group, contains those compounds wherein

[0462] A is (C₁-C₆)alkanoyl, said (C₁-C₆)alkanoyl optionally mono-, di-or tri-substituted on carbon independently with halo;

[0463] K is (C₁-C₈)alkylene;

[0464] Q is

[0465] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0466] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0467] —X—(C₂-C₅)alkylene-,

[0468] —(C₁-C₅)alkylene-X—,

[0469] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0470] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0471] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0472] M is —Ar and —Ar is phenyl, thienyl, benzofuranyl,benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl,2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentylor cyclohexyl; and

[0473] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or(C₁-C₇)alkyl.

[0474] A group of compounds which is preferred among the H2 Group ofcompounds, designated the L2 Group, contains those compounds wherein

[0475] A is (C₁-C₆)alkanoyl, said (C₁-C₆)alkanoyl optionally mono-, di-or tri-substituted on carbon independently with halo;

[0476] K is oxy(C₁-C₄)alkylene;

[0477] Q is

[0478] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0479] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0480] —X—(C₂-C₅)alkylene-,

[0481] —(C₁-C₅)alkylene-X—,

[0482] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0483] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0484] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0485] M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl,cyclopentyl or cyclohexyl; and

[0486] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or(C₁-C₇)alkyl.

[0487] A group of compounds which is preferred among the H2 Group ofcompounds, designated the M2 Group, contains those compounds wherein

[0488] A is (C₃-C₆)alkanoyl said (C₃-C₆)alkanoyl optionally mono-, di-or tri-substituted on carbon independently with halo;

[0489] K is (C₃-C₈)alkylene, said (C₃-C₈)alkylene beingmono-unsaturated;

[0490] Q is

[0491] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0492] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0493] —X—(C₂-C₅)alkylene-,

[0494] —(C₁-C₅)alkylene-X—,

[0495] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0496] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0497] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0498] M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl;and

[0499] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

[0500] A preferred group of compounds, designated the N2 Group, containsthose compounds having the Formula I as shown above wherein.

[0501] B is C(H);

[0502] A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted on carbonindependently with hydroxy or halo;

[0503] X is phenyl, thienyl, or thiazolyl said phenyl, thienyl orthiazolyl optionally mono- or di-substituted independently with fluoro,chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0504] W is oxy, thio or sulfonyl;

[0505] Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

[0506] K is (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with hydroxy, fluoro or chloro;

[0507] Ar is (C₅-C₇)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl,oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl,indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl,benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl,cyclohexyl, cyclopentyl, or chromanyl;

[0508] Ar¹ and Ar² are each independently (C₅-C₇)cycloalkyl, phenyl,thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl,isoxazolyl, pyrazinyl or pyrazolyl;

[0509] R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and

[0510] R² and R³ are each independently hydroxy, halo, difluoromethoxy,trifluoromethoxy, trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy,(C₁-C₅)alkanoyl, cyano, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl or carbamoyl.

[0511] It is especially preferred for Group N2 that K is not optionallymono-, di- or tri-substituted independently with methyl, fluoro orchloro.

[0512] A group of compounds which is preferred among the N2 Group ofcompounds, designated the O2 Group, contains those compounds wherein

[0513] A is (C₁-C₆)alkanoyl, said A optionally mono-, di- ortri-substituted on carbon independently with halo;

[0514] Q is

[0515] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0516] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0517] —X—(C₂-C₅)alkylene-,

[0518] —(C₁-C₅)alkylene-X—,

[0519] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0520] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0521] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0522] K is methylene or ethylene;

[0523] M is —Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are eachindependently phenyl, pyridyl or thienyl;

[0524] V is a bond or (C₁-C₂)alkylene;

[0525] R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said(C₁-C₄)alkyl and (C₁-C₄)alkoxy optionally mono-, di- or tri-substitutedindependently with hydroxy or fluoro; and

[0526] R² and R³ are each independently chloro or fluoro.

[0527] A group of compounds which is preferred among the N2 Group ofcompounds, designated the P2 Group, contains those compounds wherein

[0528] A is (C₁-C₆)alkanoyl, said A optionally mono-, di- ortri-substituted on carbon independently with hydroxy or halo;

[0529] K is methylene;

[0530] Q is

[0531] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0532] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0533] —X—(C₂-C₅)alkylene-,

[0534] —(C₁-C₅)alkylene-X—,

[0535] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0536] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0537] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0538] M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl,oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substitutedwith at least R¹;

[0539] R¹ is (C₁-C₇)alkyl or (C₁-C₆)alkoxy, said (C₁-C₇)alkyl or(C₁-C₆)alkoxy optionally mono-, di- or tri-substituted independentlywith hydroxy or fluoro; and

[0540] R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.

[0541] A group of compounds which is preferred among the N2 Group ofcompounds, designated the Q2 Group, contains those compounds wherein

[0542] A is (C₁-C₆)alkanoyl, said A optionally mono-, di- ortri-substituted on carbon independently with halo;

[0543] K is (C₁-C₈)alkylene;

[0544] Q is

[0545] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0546] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0547] —X—(C₂-C₅)alkylene-,

[0548] —(C₁-C₅)alkylene-X—,

[0549] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0550] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0551] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0552] M is —Ar and —Ar is phenyl, thienyl, benzofuranyl,benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl,2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentylor cyclohexyl; and

[0553] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

[0554] A group of compounds which is preferred among the N2 Group ofcompounds, designated the R2 Group, contains those compounds wherein

[0555] A is (C₁-C₆)alkanoyl said A optionally mono-, di- ortri-substituted on carbon independently with halo;

[0556] K is oxy(C₁-C₄)alkylene;

[0557] Q is

[0558] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0559] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0560] —X—(C₂-C₅)alkylene-,

[0561] —(C₁-C₅)alkylene-X—,

[0562] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0563] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0564] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0565] M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl,cyclopentyl or cyclohexyl; and

[0566] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

[0567] A group of compounds which is preferred among the N2 Group ofcompounds, designated the S2 Group, contains those compounds wherein

[0568] A is (C₁-C₆)alkanoyl, said A optionally mono-, di- ortri-substituted on carbon independently with halo;

[0569] K is (C₃-C₈)alkylene, said (C₃-C₈)alkylene beingmono-unsaturated;

[0570] Q is

[0571] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0572] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0573] —X—(C₂-C₅)alkylene-,

[0574] —(C₁-C₅)alkylene-X—,

[0575] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0576] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or

[0577] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-;

[0578] M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl;and

[0579] R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.

[0580] An especially preferred compound of the J2 Group of compounds isa compound wherein

[0581] A is propanoyl;

[0582] Q is n-hexylene;

[0583] Z is carboxyl;

[0584] K is methylene; and

[0585] M is 4-(n-1-hydroxylhexyl)phenyl.

[0586] An especially preferred compound among the H1 Group of compoundsis a compound wherein

[0587] A is methylsulfonyl;

[0588] Q is n-hexylene;

[0589] Z is 5-(1H-tetrazolyl);

[0590] K is oxyethyl; and

[0591] M is 3,5-dichlorophenyl.

[0592] An especially preferred compound among the Y1 Group of compoundsis a compound wherein

[0593] A is methylsulfonyl;

[0594] Q is 3-methylenephenylmethyl;

[0595] Z is carboxyl;

[0596] K is trans-2-n-propenylene; and

[0597] M is 3,5-dichlorophenyl.

[0598] This invention is also directed to a method for augmenting, andmaintaining bone mass and preventing further bone loss in a mammalcomprising administering to a mammal a therapeutically effective amountof a compound of Formula I or a pharmaceutically acceptable salt orprodrug thereof.

[0599] This invention is also directed to a method for treating a mammalhaving a condition which presents with low bone mass comprisingadministering to a mammal having a condition which presents with lowbone mass a therapeutically effective amount of a compound of Formula Ior a pharmaceutically acceptable salt or prodrug thereof. Preferablypost-menopausal women and men over the age of 60 are treated. Alsoincluded are individuals regardless of age who have significantlyreduced bone mass, i.e., ≧1.5 s.d. below young normal levels.

[0600] Yet another aspect of this invention is directed to methods fortreating osteoporosis, bone fractures, osteotomy, bone loss associatedwith periodontitis, or prosthetic ingrowth in a mammal (including ahuman being) comprising administering to a mammal suffering fromosteoporosis, bone fracture, osteotomy, bone loss associated withperiodontitis, or prosthetic ingrowth an osteoporosis, bone fracture,osteotomy, bone loss associated with periodontitis, or prostheticingrowth treating amount of a Formula I compound or a pharmaceuticallyacceptable salt or prodrug thereof.

[0601] Yet another aspect of this invention is directed to a method fortreating osteoporosis in a mammal (including a human being) bycomprising administering to a mammal suffering from osteoporosis anosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

[0602] Yet another aspect of this invention is directed to a method fortreating osteotomy bone loss in a mammal (including a human being)comprising administering to a mammal who underwent an osteotomyprocedure to repair bone integrity a therapeutically effective amount ofa Formula I compound or a pharmaceutically acceptable salt or prodrugthereof. In one aspect the Formula I compound is applied locally to asite of osteotomy.

[0603] Yet another aspect of this invention is directed to a method fortreating alveolar bone loss in a mammal (including a human being)comprising administering to a mammal suffering from an alveolar boneloss an alveolar bone loss treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

[0604] Yet another aspect of this invention is directed to a method fortreating bone loss associated with periodontitis in a mammal (includinga human being) comprising administering to a mammal suffering from boneloss associated with periodontitis a bone loss associated withperiodontitis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

[0605] Yet another aspect of this invention is directed to a method fortreating childhood idiopathic bone loss in a mammal comprisingadministering to a child suffering from childhood idiopathic bone loss achildhood idiopathic bone loss treating amount of a Formula I compoundor a pharmaceutically acceptable salt or prodrug thereof.

[0606] Yet another aspect of this invention is directed to a method fortreating “secondary osteoporosis”, which includes glucocorticoid-inducedosteoporosis, hyperthyroidism-induced osteoporosis,immobilization-induced osteoporosis, heparin-induced osteoporosis orimmunosuppressive-induced osteoporosis in a mammal (including a humanbeing) by administering to a mammal suffering from “secondaryosteoporosis” a “secondary osteoporosis” treating amount of a Formula Icompound or a pharmaceutically acceptable salt or prodrug thereof.

[0607] Yet another aspect of this invention is directed to a method fortreating glucocorticoid-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromglucocorticoid-induced osteoporosis a glucocorticoid-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

[0608] Yet another aspect of this invention is directed to a method fortreating hyperthyroidism-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromhyperthyroidism-induced osteoporosis a hyperthyroidism-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

[0609] Yet another aspect of this invention is directed to a method fortreating immobilization-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromimmobilization-induced osteoporosis a immobilization-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

[0610] Yet another aspect of this invention is directed to a method fortreating heparin-induced osteoporosis in a mammal (including a humanbeing) comprising administering to a mammal suffering fromheparin-induced osteoporosis a heparin-induced osteoporosis treatingamount of a Formula I compound or a pharmaceutically acceptable salt orprodrug thereof.

[0611] Yet another aspect of this invention is directed to a method fortreating immunosuppressive-induced osteoporosis in a mammal (including ahuman being) comprising administering to a mammal suffering fromimmunosuppressive-induced osteoporosis an immunosuppressive-inducedosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof.

[0612] Yet another aspect of this invention is directed to a method fortreating a bone fracture in a mammal (including a human being)comprising administering to a mammal suffering from a bone fracture abone fracture treating amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof. In one aspect ofthis invention for treating a bone fracture the Formula I compound or apharmaceutically acceptable salt or prodrug thereof is applied locallyto the site of bone fracture. In another aspect of this invention theFormula I compound or a pharmaceutically acceptable salt or prodrugthereof is administered systemically.

[0613] Yet another aspect of this invention is directed to a method forenhancing bone healing following facial reconstruction or maxillaryreconstruction or mandibular reconstruction in a mammal (including ahuman being) comprising administering to a mammal which has undergonefacial reconstruction or maxillary reconstruction or mandibularreconstruction a bone enhancing amount of a Formula I compound or apharmaceutically acceptable salt or prodrug thereof. In one aspect ofthis method the Formula I compound or a pharmaceutically acceptable saltor prodrug thereof is applied locally to the site of bonereconstruction.

[0614] Yet another aspect of this invention is directed to a method forinducing prosthetic ingrowth in a mammal (including a human being)comprising administering to a mammal a therapeutically effective amountof a Formula I compound or a pharmaceutically acceptable salt or prodrugthereof.

[0615] Yet another aspect of this invention is directed to a method forinducing vertebral synostosis in a mammal (including a human being)comprising administering to a mammal undergoing surgery for vertebralsynostosis a therapeutically effective amount of a Formula I compound ora pharmaceutically acceptable salt or prodrug thereof.

[0616] Yet another aspect of this invention is directed to a method forenhancing long bone extension in a mammal (including a human being)comprising administering to a mammal suffering from an insufficientlysized long bone a long bone enhancing amount of a Formula I compound ora pharmaceutically acceptable salt or prodrug thereof.

[0617] Yet another aspect of this invention is directed to a method foruse in place of a bone graft in a mammal (including a human being)comprising administering to a mammal a therapeutically effective amountof a Formula I compound or a pharmaceutically acceptable salt or prodrugthereof. In one aspect of this method the Formula I compound or apharmaceutically acceptable salt or prodrug thereof is applied locallyto the site of a bone graft. Also, if bone graft is needed, an amount ofa Formula I compound or a pharmaceutically acceptable salt or prodrugthereof can be applied to the site of a bone graft to restore bone.

[0618] A preferred dosage is about 0.001 to 100 mg/kg/day of the FormulaI compound or a pharmaceutically acceptable salt or prodrug thereof. Anespecially preferred dosage is about 0.01 to 10 mg/kg/day of the FormulaI compound or a pharmaceutically acceptable salt or prodrug thereof.

[0619] This invention is also directed to pharmaceutical compositionswhich comprise a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0620] This invention is also directed to pharmaceutical compositionsfor the augmentation of bone mass which comprise a bone massaugmentating amount of a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier.

[0621] This invention is also directed to pharmaceutical compositionsfor the treatment of a condition which presents with low bone mass in amammal (including a human being) which comprise a low bone masscondition treating amount of a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0622] This invention is also directed to pharmaceutical compositionsfor the treatment of osteoporosis, bone fractures, osteotomy, bone lossassociated with periodontitis, bone graft substitution or prostheticingrowth in a mammal (including a human being) which comprises atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0623] This invention is also directed to pharmaceutical compositionsfor the treatment of “secondary osteoporosis”, which includesglucocorticoid-induced osteoporosis, hyperthyroidism-inducedosteoporosis, immobilization-induced osteoporosis, heparin-inducedosteoporosis or immunosuppressive-induced osteoporosis in a mammal(including a human being) which comprise a “secondary osteoporosis”treating amount of a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier.

[0624] This invention is also directed to pharmaceutical compositionsfor the treatment of osteoporosis in a mammal (including a human being)which comprise an osteoporosis treating amount of a compound of theFormula I or a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0625] This invention is also directed to pharmaceutical compositionsfor enhancing bone fracture healing in a mammal (including a humanbeing) which comprise a bone fracture treating amount of a compound ofthe Formula I or a pharmaceutically acceptable salt or prodrug thereofand a pharmaceutically acceptable carrier.

[0626] This invention is also directed to pharmaceutical compositionsfor the treatment of osteotomy bone loss in a mammal (including a humanbeing) which comprise an osteotomy bone loss treating amount of acompound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

[0627] This invention is also directed to pharmaceutical compositionsfor the treatment of alveolar bone loss in a mammal (including a humanbeing) which comprise an alveolar bone loss treating amount of acompound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

[0628] This invention is also directed to pharmaceutical compositionsfor the treatment of childhood idiopathic bone loss in a child whichcomprises a childhood idiopathic bone loss treating amount of a compoundof the Formula I or a pharmaceutically acceptable salt or prodrugthereof and a pharmaceutically acceptable carrier.

[0629] This invention is also directed to pharmaceutical compositionsfor the augmentation of bone healing following facial reconstruction ormaxillary reconstruction or mandibular reconstruction in a mammal(including a human being) which comprise a bone healing treating amountof a compound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

[0630] This invention is also directed to pharmaceutical compositionsfor the treatment of bone loss associated with periodontitis in a mammal(including a human being) which comprise a bone loss associated withperiodontitis treating amount of a compound of the Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0631] This invention is also directed to pharmaceutical compositionsfor the treatment of prosthetic ingrowth in a mammal (including a humanbeing) which comprise a prosthetic ingrowth treating amount of acompound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

[0632] This invention is also directed to pharmaceutical compositionsfor inducing vertebral synostosis in a mammal (including a human being)which comprise a therapeutically effective amount of a compound of theFormula I or a pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0633] This invention is also directed to pharmaceutical compositionsfor the augmentation of long bone extension in a mammal (including ahuman being) which comprise bone mass augmentation treating amount of acompound of the Formula I or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

[0634] This invention is also directed to pharmaceutical compositionsfor the treatment of glucocorticoid-induced osteoporosis in a mammal(including a human being) which comprise a glucocorticoid-inducedosteoporosis treating amount of a compound of the Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0635] This invention is also directed to pharmaceutical compositionsfor the treatment of hyperthyroidism-induced osteoporosis in a mammal(including a human being) which comprise a hyperthyroidism-inducedosteoporosis treating amount of a compound of the Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0636] This invention is also directed to pharmaceutical compositionsfor the treatment of immobilization-induced osteoporosis in a mammal(including a human being) which comprise a immobilization-inducedosteoporosis treating amount of a compound of the Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0637] This invention is also directed to pharmaceutical compositionsfor the treatment of heparin-induced osteoporosis in a mammal (includinga human being) which comprise a heparin-induced osteoporosis treatingamount of a compound of the Formula I or a pharmaceutically acceptablesalt or prodrug thereof and a pharmaceutically acceptable carrier.

[0638] This invention is also directed to pharmaceutical compositionsfor the treatment of immunosuppressive-induced osteoporosis in a mammal(including a human being) which comprise a immunosuppressive-inducedosteoporosis treating amount of a compound of the Formula I or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.

[0639] Yet another aspect of this invention are combinations of theFormula I compounds or a pharmaceutically acceptable salt or prodrugthereof and other compounds as described below.

[0640] Yet another aspect of this invention is directed to apharmaceutical compositions comprising a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof and ananti-resorptive agent and for the use of such compositions for thetreatment (e.g., prevention) of conditions which present with low bonemass, including osteoporosis in mammals (e.g., humans, particularlywomen) or the use of such compositions for other bone mass augmentinguses.

[0641] The combinations of this invention comprises a therapeuticallyeffective amount of a first compound, said first compound being aFormula I compound or a pharmaceutically acceptable salt or prodrugthereof; and a therapeutically effective amount of a second compound,said second compound being an anti-resorptive agent such as an estrogenagonist/antagonist or a bisphosphonate.

[0642] Preferred estrogen agonist/antagonists include droloxifene,raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman,levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,

[0643]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0644](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0645]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0646]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[0647]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0648]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;and

[0649]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand the pharmaceutically acceptable salts thereof.

[0650] Especially preferred estrogen agonist/antagonists includedroloxifene;

[0651]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0652](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0653]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0654]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[0655]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0656]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0657]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof.

[0658] Preferred bisphosphonates include, tiludronic acid, alendronicacid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid,and pamidronic acid and their pharmaceutically acceptable salts.

[0659] Another aspect of this invention is a method for treating mammalswhich present with low bone mass comprising administering to a mammalhaving a condition which presents with low bone mass

[0660] a. a therapeutically effective amount of a first compound, saidfirst compound being a Formula I compound or a pharmaceuticallyacceptable salt or prodrug thereof; and

[0661] b. a therapeutically effective amount of a second compound, saidsecond compound being an anti-resorptive agent such as an estrogenagonist/antagonist or a bisphosphonate.

[0662] Such compositions and methods may also be used for other bonemass augmenting uses.

[0663] Preferred estrogen agonist/antagonists in this method includedroloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene,centchroman, levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,

[0664]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0665](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0666]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0667]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[0668]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0669]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0670]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof.

[0671] Especially preferred estrogen agonist/antagonists includedroloxifene;

[0672]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0673](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0674]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0675]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[0676]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0677]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0678]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineand the pharmaceutically acceptable salts thereof

[0679] Preferred bisphosphonates include, tiludronic acid, alendronicacid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid,and pamidronic acid and their pharmaceutically acceptable salts.

[0680] A preferred aspect of this method is wherein the condition whichpresents with low bone mass is osteoporosis.

[0681] Another preferred aspect of this method is wherein the firstcompound and the second compound are administered substantiallysimultaneously.

[0682] Another preferred aspect of this method is wherein the firstcompound is administered for a period of from about one week to aboutthree years.

[0683] Optionally the administration of the first compound is followedby administration of the second compound wherein the second compound isan estrogen agonist/antagonist for a period of from about three monthsto about three years without the administration of the first compoundduring the second period of from about three months to about threeyears.

[0684] Alternatively, the administration of the first compound isfollowed by administration of the second compound wherein the secondcompound is an estrogen agonist/antagonist for a period greater thanabout three years without the administration of the first compoundduring the greater than about three year period.

[0685] Another aspect of this invention is a kit comprising:

[0686] a. a therapeutically effective amount of a Formula I compound ora pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier in a first unit dosage form;

[0687] b. a therapeutically effective amount of an anti-resorptive agentsuch as an estrogen agonist/antagonist or a bisphosphonate and apharmaceutically acceptable carrier in a second unit dosage form; and

[0688] c. container means for containing said first and second dosageforms.

[0689] Preferred estrogen agonist/antagonists in this kit includedroloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene,centchroman, levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,

[0690]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0691](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0692]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0693]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[0694]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0695]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0696]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof.

[0697] Especially preferred estrogen agonist/antagonists includedroloxifene;

[0698]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0699](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0700]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0701]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[0702]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0703]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0704]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;and the pharmaceutically acceptable salts thereof

[0705] Preferred bisphosphonates include, tiludronic acid, alendronicacid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid,and pamidronic acid and their pharmaceutically acceptable salts.

[0706] Yet another aspect of this invention is directed to apharmaceutical composition including a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof and another boneanabolic agent (although the other bone anabolic agent may be adifferent Formula I compound) and for the use of such compositions forthe treatment of conditions which present with low bone mass, includingosteoporosis in mammals (e.g., humans, particularly women) or the use ofsuch compositions for other bone mass augmenting uses.

[0707] The combination comprises a therapeutically effective amount of afirst compound, said first compound being a Formula I compound or apharmaceutically acceptable salt or prodrug thereof; and atherapeutically effective amount of a second compound, said secondcompound being another bone anabolic agent.

[0708] Preferred bone anabolic agents include IGF-1 optionally withIGF-1 binding protein 3, prostaglandin, prostaglandinagonist/antagonist, sodium fluoride, parathyroid hormone (PTH), activefragments of parathyroid hormone, parathyroid hormone related peptidesand active fragments and analogues of parathyroid hormone relatedpeptides, growth hormone or growth hormone secretagogues and thepharmaceutically acceptable salts thereof.

[0709] Another aspect of this invention is a method for treating mammalswhich present with low bone mass comprising administering to a mammalhaving a condition which presents with low bone mass

[0710] a. a therapeutically effective amount of a first compound, saidfirst compound being a Formula I compound or a pharmaceuticallyacceptable salt or prodrug therof; and

[0711] b. a therapeutically effective amount of a second compound, saidsecond compound being another bone anabolic agent other than the FormulaI compound.

[0712] Such compositions and methods may also be used for other bonemass augmenting uses.

[0713] Preferred bone anabolic agents include IGF-1 optionally withIGF-1 binding protein 3, prostaglandin, prostaglandinagonist/antagonist, sodium fluoride, parathyroid hormone (PTH), activefragments of parathyroid hormone, parathyroid hormone related peptidesand active fragments and analogues of parathyroid hormone relatedpeptides, growth hormone or growth hormone secretagogues and thepharmaceutically acceptable salts thereof

[0714] A preferred aspect of this method is wherein the condition whichpresents with low bone mass is osteoporosis.

[0715] Another preferred aspect of this method is wherein the firstcompound and the second compound are administered substantiallysimultaneously.

[0716] Another aspect of this invention is a kit comprising:

[0717] a. a therapeutically effective amount of a Formula I compound ora pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier in a first unit dosage form;

[0718] b. a therapeutically effective amount of a second compound, saidsecond compound being a bone anabolic agent other than the Formula Icompound; and

[0719] c. container means for containing said first and second dosageforms.

[0720] Preferred bone anabolic agents include IGF-1 optionally withIGF-1 binding protein 3, prostaglandin, prostaglandinagonist/antagonist, sodium fluoride, parathyroid hormone (PTH), activefragments of parathyroid hormone, parathyroid hormone related peptidesand active fragments and analogues of parathyroid hormone relatedpeptides, growth hormone or growth hormone secretagogues and thepharmaceutically acceptable salts thereof.

[0721] A preferred group of compounds, designated the T2 Group, containsthose compounds having the Formula I as shown above wherein

[0722] B is N;

[0723] A is (C₁-C₃) alkylsulfonyl;

[0724] Q is

[0725] —(C₃-C₅)alkylene-O—(C₁-C₃)alkylene-,

[0726] —(C₅-C₇)alkylene-, said —(C₅-C₇)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0727] —(C₂-C₄)alkylene-X—,

[0728] —(CH₂)-meta-phenylene-O—(CH₂)— optionally mono- or di-substitutedindependently with methoxy, trifluoromethyl, difluoromethoxy,trifluoromethoxy, chloro or fluoro

[0729] or

[0730] —(CH₂)-meta-phenylene-(CH₂)— optionally mono- or di-substitutedindependently with methoxy, trifluoromethyl, difluoromethoxy,trifluoromethoxy, chloro or fluoro;

[0731] M is —Ar¹—V—Ar² or —Ar¹—O—Ar²;

[0732] V is a bond or —CH₂—;

[0733] Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl;

[0734] X is thienyl, thiazolyl, or furanyl;

[0735] K is methylene;

[0736] Ar¹ is phenyl, (C₅-C₇)cycloalkyl, furanyl, thienyl, thiazolyl, orpyridyl;

[0737] Ar² is (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl,triazolyl or pyrazolyl;

[0738] R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said(C₁-C₄)alkyl and (C₁-C₄)alkoxy optionally mono-, di- or tri-substitutedindependently with hydroxy or fluoro; and

[0739] R² and R³ are each independently, methoxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, chloro or fluoro.

[0740] A group of compounds which is preferred among the T2 group ofcompounds, designated the U2 Group, contains those compounds wherein

[0741] Q is

[0742] —(CH₂)-meta-phenylene-(CH₂)—,

[0743] M is —Ar¹—Ar²,

[0744] Ar¹ is phenyl;

[0745] Ar² is (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl, said Ar² optionally mono- or di-substituted independentlywith R¹ or R²;

[0746] R¹ is chloro, fluoro, methyl, methoxy, trifluoromethyl,difluoromethoxy or trifluoromethoxy; and

[0747] R² is methoxy, chloro or fluoro.

[0748] A group of compounds which is preferred among the T2 group ofcompounds, designated the V2 Group, contains those compounds wherein

[0749] Q is

[0750] —(CH₂)-meta-phenylene-O—(CH₂)—,

[0751] M is —Ar¹—Ar²,

[0752] Ar¹ is phenyl;

[0753] Ar² is (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl, said Ar optionally mono- or di-substituted independently withR¹ or R²;

[0754] R¹ is chloro, fluoro, methyl, methoxy, trifluoromethyl,difluoromethoxy or trifluoromethoxy; and

[0755] R² is methoxy, chloro or fluoro.

[0756] An especially preferred compound of the U2 Group of compounds isa compound wherein

[0757] A is methylsulfonyl;

[0758] Z is carboxyl; and

[0759] M is 4-(cyclohexyl)phenyl.

[0760] An especially preferred compound of the U2 Group of compounds isa compound wherein

[0761] A is methylsulfonyl;

[0762] Z is carboxyl; and

[0763] M is 4-(thiazol-2-yl)phenyl.

[0764] An especially preferred compound of the U2 Group of compounds isa compound wherein

[0765] A is methylsulfonyl;

[0766] Z is carboxyl; and

[0767] M is 4-(pyrazin-2-yl)phenyl.

[0768] Especially preferred compounds among the U2 Group are

[0769] a.(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid;

[0770] b.(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid; or

[0771] c.(3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid.

[0772] A preferred group of compounds, designated the W2 Group, containsthose compounds having the Formula I as shown above wherein

[0773] B is N;

[0774] A is (C₁-C₃)alkylsulfonyl;

[0775] Q is —(C₂-C₄)alkylene-X—;

[0776] X is thiazolyl or furanyl; said thiazolyl or furanyl optionallymono- or di-substituted independently with methyl, methoxy, fluoro,chloro, trifluoromethyl, difluoromethoxy or trifluoromethoxy;

[0777] K is oxy-ethylene or propylene, said propylene optionally beingmono-unsaturated;

[0778] M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl,oxazolyl, isoxazolyl, pyrimidyl, imidazolyl, cyclohexyl, cyclopentyl,cyclobutyl, or cycloheptyl;

[0779] R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and

[0780] R² and R³ are each independently methoxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, chloro or fluoro.

[0781] A group of compounds which is preferred among the W2 group ofcompounds, designated the X2 Group, contains those compounds wherein

[0782] A is methylsulfonyl;

[0783] Z is carboxyl, or (C₁-C₄)alkoxycarbonyl;

[0784] Q is -propylene-X—;

[0785] X is thiazolyl;

[0786] K is oxy-ethylene or propylene;

[0787] M is phenyl optionally mono- or di-substituted independently withfluoro, chloro, methoxy, methyl, difluoromethoxy, trifluoromethoxy ortrifluoromethyl.

[0788] An especially preferred compound of the X2 Group of compounds isa compound wherein

[0789] Z is carboxyl;

[0790] K is propylene; and

[0791] M is 3-(chloro)phenyl.

[0792] An especially preferred compound of the X2 Group of compounds isa compound wherein

[0793] Z is carboxyl;

[0794] K is oxy-ethylene; and

[0795] M is 3,5-dichlorophenyl.

[0796] Especially preferred compounds among the X2 Group are

[0797] a.2-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid; or

[0798] b.2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid.

[0799] Another aspect of this invention is directed to a compound ofFormula IA

[0800] or a pharmaceutically acceptable salt or prodrugs thereof whereineither (i):

[0801] B is N;

[0802] A is (C₁-C₆)alkylsulfonyl, (C₃-C₇)cycloalkylsulfonyl,(C₃-C₇)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di- or tri-substituted on carbon independently with hydroxy,(C₁-C₄)alkyl or halo;

[0803] Q is

[0804] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0805] —(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0806] —X—(C₁-C₅)alkylene-,

[0807] —(C₁-C₅)alkylene-X—,

[0808] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0809] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,

[0810] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,

[0811] —(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the twooccurrences of W are independent of each other,

[0812] —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

[0813] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,

[0814] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,

[0815] —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or

[0816] —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-;

[0817] W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N—(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

[0818] X is a five or six membered aromatic ring optionally having oneor two heteroatoms selected independently from oxygen, nitrogen, andsulfur; said ring optionally mono-, or di-substituted independently withhalo, (C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy,difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

[0819] Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl,(C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;

[0820] K is a bond, (C₁-C₈)alkylene, thio(C₁-C₄)alkylene oroxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionally mono-unsaturated andwherein K is optionally mono-, di- or tri-substituted independently withfluoro, methyl or chloro;

[0821] M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar², —Ar¹O—Ar², —Ar¹—S—(C₁-C₃)—Ar²—,—Ar¹—(C₁-C₃)—S—Ar²— or —Ar¹—(C₁-C₃)—S—(C₁-C₃)—Ar², wherein Ar, Ar¹ andAr² are each independently a partially saturated, fully saturated orfully unsaturated five to eight membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated five or six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0822] said Ar, Ar¹ and Ar² moieties optionally substituted, on one ringif the moiety is monocyclic, or one or both rings if the moiety isbicyclic, on carbon, nitrogen or sulfur with up to three substituentsindependently selected from R¹, R² and R³ wherein R¹, R² and R³ are oxo,hydroxy, nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl,(C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl;

[0823] R¹, R² and R³ are optionally mono-, di- or tri-substituted oncarbon independently with halo or hydroxy; and

[0824] V is a bond or (C₁-C₃)alkylene optionally mono-unsaturated andoptionally mono- or di-substituted independently with hydroxy or fluoro,

[0825] with the proviso that when K is (C₂-C₄)alkylene and M is Ar andAr is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-ylthen said (C₅-C₈)cycloalkyl substituents are not substituted at the oneposition with hydroxy;

[0826] or (ii):

[0827] B is N;

[0828] A is (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said Amoieties optionally mono-, di- or tri-substituted independently oncarbon with hydroxy or halo;

[0829] Q is

[0830] —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,

[0831] —(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substitutedwith up to four substituents independently selected from fluoro or(C₁-C₄)alkyl,

[0832] —X—(C₂-C₅)alkylene-,

[0833] —(C₁-C₅)alkylene-X—,

[0834] —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,

[0835] —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,

[0836] —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,

[0837] —(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the twooccurrences of W are independent of each other,

[0838] —(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,

[0839] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,

[0840] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,

[0841] —(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,

[0842] —(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-;

[0843] W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-,-mono-N—(C₁-C₄)alkyleneaminosulfonyl-, sulfonylamino,N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines;

[0844] X is a five or six membered aromatic ring optionally having oneor two heteroatoms selected independently from oxygen, nitrogen, andsulfur; said ring optionally mono-, or di-substituted independently withhalo, (C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy,difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, or carbamoyl;

[0845] Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl,(C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;

[0846] K is (C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene,said (C₁-C₈)alkylene optionally mono-unsaturated and wherein K isoptionally mono-, di- or tri-substituted independently with fluoro,methyl or chloro;

[0847] M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar², —Ar¹—O—Ar²,—Ar¹—S—(C₁-C₃)—Ar²—, —Ar¹—(C₁-C₃)—S—Ar²— or —Ar¹—(C₁-C₃)—S—(C₁-C₃)—Ar²wherein Ar, Ar¹ and Ar² are each independently a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated five or sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;

[0848] said Ar, Ar¹ and Ar² moieties optionally substituted, on one ringif the moiety is monocyclic, or one or both rings if the moiety isbicyclic, on carbon, nitrogen or sulfur with up to three substituentsindependently selected from R¹, R² and R³ wherein R¹, R² and R³ are oxo,H, hydroxy, nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl,(C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl;

[0849] R¹, R² and R³ are optionally mono-, di- or tri-substitutedindependently on carbon with halo or hydroxy; and

[0850] V is a bond or (C₁-C₃)alkylene optionally mono-unsaturated andoptionally mono- or di-substituted independently with hydroxy or fluoro

[0851] with the proviso that when K is (C₂-C₄)alkylene and M is Ar andAr is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl thensaid (C₅-C₈)cycloalkyl substituents are not substituted at the oneposition with hydroxy

[0852] and with the proviso that6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and itsethyl ester are not included.

[0853] Yet another aspect of this invention is directed to apharmaceutical composition comprising:

[0854] a therapeutically effective amount of a compound of Formula IA ora pharmaceutically acceptable salt or prodrug thereof and atherapeutically effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-or a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharamceutically acceptable salt thereof.

[0855] Yet another aspect of this invention is directed to a method fortreating a mammal having a condition which presents with low bone masscomprising administering to said mammal

[0856] a therapeutically effective amount of a compound of Formula IA ora pharmaceutically acceptable salt or prodrug thereof and atherapeutically effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olor a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharamceutically acceptable salt thereof.

[0857] Yet another aspect of this invention is directed to a kitcomprising

[0858] a therapeutically effective amount of a compound of Formula IA ora pharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier in a first unit dosage form;

[0859] a therapeutically effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olor a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharamceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier in a second unit dosage form; and

[0860] container means for containing said first and second dosageforms.

[0861] Yet another aspect of this invention is directed to a method fortreating a mammal in need of kidney regeneration comprisingadministering to said mammal a therapeutically effective amount of acompound of Formula 1A or a pharmaceutically acceptable salt or prodrugthereof.

[0862] Yet another aspect of this invention is directed to a method fortreating a mammal having a condition which presents with low bone masscomprising administering to said mammal a therapeutically effectiveamount of a compound of Formula IA or a pharmaceutically acceptable saltor prodrug thereof.

[0863] Yet another aspect of this invention is directed to apharmaceutical composition which comprises a therapeutically effectiveamount of a compound of Formula IA or a pharmaceutically acceptable saltor prodrug thereof and a pharmaceutically acceptable carrier.

[0864] Yet another aspect of this invention is directed to a method forlowering intraocular pressure in a mammal comprising administering atherapeutically effective amount of a compound of Formula IA or apharamaceutically acceptable salt or prodrug thereof to a mammal inneed.

[0865] The phrase “condition(s) which presents with low bone mass”refers to a condition where the level of bone mass is below the agespecific normal as defined in standards by the World Health Organization“Assessment of Fracture Risk and its Application to Screening forPostmenopausal Osteoporosis (1994). Report of a World HealthOrganization Study Group. World Health Organization Technical Series843”. Included in “condition(s) which presents with low bone mass” areprimary and secondary osteoporosis. Secondary osteoporosis includesglucocorticoid-induced osteoporosis, hyperthyroidism-inducedosteoporosis, immobilization-induced osteoporosis, heparin-inducedosteoporosis and immunosuppressive-induced osteoporosis. Also includedis periodontal disease, alveolar bone loss, osteotomy and childhoodidiopathic bone loss. The “condition(s) which presents with low bonemass” also includes long term complications of osteoporosis such ascurvature of the spine, loss of height and prosthetic surgery.

[0866] The phrase “condition which presents with low bone mass” alsorefers to a mammal known to have a significantly higher than averagechance of developing such diseases as are described above includingosteoporosis (e.g., post-menopausal women, men over the age of 60).

[0867] Other bone mass augmenting or enhancing uses include increasingthe bone fracture healing rate, enhancing the rate of successful bonegrafts, bone healing following facial reconstruction or maxillaryreconstruction or mandibular reconstruction, prosthetic ingrowth,vertebral synostosis or long bone extension.

[0868] Those skilled in the art will recognize that the term bone massactually refers to bone mass per unit area which is sometimes (althoughnot strictly correctly) referred to as bone mineral density.

[0869] The term “treating”, “treat” or “treatment” as used hereinincludes preventative (e.g., prophylactic) and palliative treatment.

[0870] By “pharmaceutically acceptable” it is meant the carrier,diluent, excipients, and/or salt must be compatible with the otheringredients of the formulation, and not deleterious to the recipientthereof.

[0871] The expression “prodrug” refers to compounds that are drugprecursors which following administration, release the drug in vivo viasome chemical or physiological process (e.g., a prodrug on being broughtto the physiological pH or through enzyme action is converted to thedesired drug form). Exemplary prodrugs upon cleavage release thecorresponding free acid, and such hydrolyzable ester-forming residues ofthe Formula I compounds include but are not limited to substituentswherein the Z moiety is independently carboxyl and the free hydrogen isreplaced by (C₁-C₄)alkyl, (C₂-C₇)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as b-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[0872] Exemplary five to six membered aromatic rings optionally havingone or two heteroatoms selected independently from oxygen, nitrogen andsulfur (i.e., X rings) are phenyl, furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl,pyridiazinyl, pyrimidinyl and pyrazinyl.

[0873] Exemplary partially saturated, fully saturated or fullyunsaturated five to eight membered rings optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen(i.e., Ar, Ar¹ and Ar²) are cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and phenyl. Further exemplary five membered rings are furyl,thienyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl,2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl,3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl,1,3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatrizaolyl,3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl,1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.

[0874] Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl,pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-trizainyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl,6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl,4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl,p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyland 1,3,5,2-oxadiazinyl. Further exemplary seven membered rings areazepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.

[0875] Further exemplary eight membered rings are cyclooctyl,cyclooctenyl and cyclooctadienyl.

[0876] Exemplary bicyclic rings consisting of two fused partiallysaturated, fully saturated or fully unsaturated five or six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen are indolizinyl,indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl,cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl,isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl,indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl,purinyl, 4Hquinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl,2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl,pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and4H-1,4-benzoxazinyl.

[0877] By alkylene is meant saturated hydrocarbon (straight chain orbranched) wherein a hydrogen atom is removed from each of the terminalcarbons. Exemplary of such groups (assuming the designated lengthencompases the particular example) are methylene, ethylene, propylene,butylene, pentylene, hexylene, heptylene).

[0878] By halo is meant chloro, bromo, iodo, or fluoro.

[0879] By alkyl is meant straight chain saturated hydrocarbon orbranched saturated hydrocarbon. Exemplary of such alkyl groups (assumingthe designated length encompasses the particular example) are methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl,isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

[0880] By alkoxy is meant straight chain saturated alkyl or branchedsaturated alkyl bonded through an oxy. Exemplary of such alkoxy groups(assuming the designated length encompasses the particular example) aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy,isohexoxy, heptoxy and octoxy.

[0881] As used herein the term mono-N— or di-N,N—(C₁-C_(x))alkyl . . .refers to the (C₁-C_(x))alkyl moiety taken independently when it isdi-N,N—(C₁-C_(x))alkyl . . . (x refers to integers).

[0882] Unless otherwise stated the “M” moieties defined above areoptionally substituted (e.g., the mere listing of a substituent such asR¹ in a subgenus or dependent claim does not mean that M is alwayssubstituted with the R¹ moiety unless it is stated that the M moiety issubstituted with R¹).

[0883] It is to be understood that if a carbocyclic or heterocyclicmoiety may be bonded or otherwise attached to a designated substrate,through differing ring atoms without denoting a specific point ofattachment, then all possible points are intended, whether through acarbon atom or, for example, a trivalent nitrogen atom. For example, theterm “pyridyl” means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-,or 3-thienyl, and so forth.

[0884] The expression “pharmaceutically-acceptable salt” refers tonontoxic anionic salts containing anions such as (but not limited to)chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate,maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate,methanesulfonate and 4-toluene-sulfonate. The expression also refers tonontoxic cationic salts such as (but not limited to) sodium, potassium,calcium, magnesium, ammonium or protonated benzathine(N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine,ethylenediamine, meglamine (N-methyl-glucamine), benethamine(N-benzylphenethylamine), piperazine or tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol).

[0885] As used herein, the expressions “reaction-inert solvent” and“inert solvent” refers to a solvent which does not interact withstarting materials, reagents, intermediates or products in a mannerwhich adversely affects the yield of the desired product.

[0886] The parenthetical negative or positive sign used herein in thenomenclature denotes the direction plane polarized light is rotated bythe particular stereoisomer.

[0887] The chemist of ordinary skill will recognize that certaincompounds of this invention will contain one or more atoms which may bein a particular stereochemical or geometric configuration, giving riseto stereoisomers and configurational isomers. All such isomers andmixtures thereof are included in this invention. Hydrates of thecompounds of this invention are also included.

[0888] The chemist of ordinary skill will recognize that certaincombinations of heteroatom-containing substituents listed in thisinvention define compounds which will be less stable under physiologicalconditions (e.g., those containing acetal or aminal linkages).Accordingly, such compounds are less preferred.

[0889] DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTAmeans ethylenediamine tetraacetic acid.

[0890] The methods and compounds of this invention result in boneformation resulting in decreased fracture rates. This invention makes asignificant contribution to the art by providing compounds and methodsthat increase bone formation resulting in prevention, retardation,and/or regression of osteoporosis and related bone disorders.

[0891] Other features and advantages will be apparent from thespecification and claims which describe the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0892] In the DETAILED DESCRIPTION OF THE INVENTION reference to“Formula I” is to be interpreted as reference to “Formula I or FormulaIA” in order to encompass the subject matter added in thiscontinuation-in-part.

[0893] In general the compounds of this invention can be made byprocesses which include processes known in the chemical arts,particularly in light of the description contained herein. Certainprocesses for the manufacture of the compounds of this invention areprovided as further features of the invention and are illustrated by thefollowing reaction schemes. Other processes may be described in theexperimental section.

[0894] Some substituents (e.g., carboxyl) may best be prepared throughconversion of another functional group (for carboxyl examples arehydroxyl or carboxaldehyde) at a point later in the synthetic sequence.

[0895] In general, the Formula I compounds wherein B is nitrogen can beprepared by sequential alkylation of sulfonamide or amide with twoappropriate alkyl halides or alkylsulfonates; or reductive amination ofan amine containing the necessary acidic functionality (suitablyprotected) with an aldehyde followed by reaction with an acylating agentor a sulfonyl chloride followed by hydrolysis.

[0896] Generally, the compounds of Formula I (wherein B is N (nitrogen)and A, K, M and Q are as described in the Summary) can be preparedaccording to the methods described in SCHEMES 1 and 2 below. In general,the sequences involve sequential alkylation of the appropriate formula 1sulfonamide or amide with two appropriate alkyl halides oralkylsulfonates. It is noted that SCHEMES 1 and 2 merely differ in theorder of addition of the two alkylating agents. The alkylation order istypically chosen depending on the reactivity of the electrophilicside-chain. In order to reduce the amount of dialkylation which occursin the first alkylation step, the less reactive electrophilic side-chainis typically introduced first. One of the alkylating agents typicallycontains a carboxylic acid or acid isostere suitably masked with anappropriate protecting group. In SCHEMES 1 and 2, the formula 3 acidprecursor is a carboxylic ester where R represents either a straightchain lower alkyl, preferably methyl or ethyl, or a tert-butyl or phenylgroup. Other acid isosteres can be employed by appropriately modifyingthese SCHEMES using methods known to those skilled in the art (seeSCHEME 6 which describes a tetrazol preparation for an example). Typicalalkylating agents are primary, secondary, benzylic or allylic and arepreferably alkyl bromides or alkyl iodides.

[0897] The formula 1 sulfonamide or amide is converted to its anion witha strong base such as sodium hydride, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassiumtert-butoxide, etc. in an aprotic solvent such as dimethylformamide,tetrahydrofuran (THF) or dimethylformamide/benzene at a temperature ofabout −78° C. to about 100° C. The resulting anion is alkylated with theappropriate formula 2 or 3 alkyl halide or alkyl sulfonate (wherein X′is the halide or sulfonate) at a temperature of about 0° C. to about100° C. to yield the corresponding alkylated formula 4 or 5 compound. Insome cases, varying amounts of a side-product resulting fromdialkylation of the amide or sulfonamide are obtained and can be removedusing chromatographic techniques, preferably by flash chromatography (W.C. Still, M. Kahn, A. Mitra, J. Org. Chem. 43, 2923, 1978). The formula4 or 5 compounds are converted to the anion again using a suitable basesuch as sodium hydride, lithium bis(trimethylsilyl)amide, lithiumdiisopropylamide, potassium bis(trimethylsilyl)amide, potassiumtert-butoxide, or potassium carbonate in an aprotic solvent such asdimethylformamide, THF, dimethylformamide/benzene, or acetone at atemperature of about −78° C. to about 100° C. Alkylation (as describedabove) with the appropriate second alkyl halide or alkyl sulfonate(formula 3 or 2 compound) provides the corresponding formula 6 ester.The formula 6 ester is hydrolyzed to the corresponding Formula I acid(in cases where R represents methyl or ethyl) with a dilute aqueousbasic solution (preferably sodium or potassium hydroxide in aqueousmethanol or ethanol), lithium hydroxide in aqueous alcoholic solvent,aqueous tetrahydrofuran at a temperature of about 0° C. to about 80° C.,or by using methods described in “Protecting Groups in OrganicSynthesis,” Second Edition, T. W. Greene and P. G. M. Wuts, John Wileyand Sons, Inc., 1991.

[0898] Formula I compounds (e.g., formula 13 or 14 compounds wherein Bis N and A, K, M, Q and Z are as defined in the Summary) can also beprepared from amines (see SCHEMES 3-4 for examples). Generally, theappropriate amine starting materials (formula 9 and 10 compounds) can becommercially obtained or can be prepared using methods known to thoseskilled in the art (see “The Chemistry of Amino, Nitroso and NitroCompounds and their Derivatives,” Ed. S. Patai, J. Wiley, New York,1982). For example, according to SCHEMES 3 and 4, the amine startingmaterials may be prepared from the corresponding formula 7 or 8nitrites. Nitriles are either available from commercial sources or canbe prepared using methods known to those skilled in the art (seeRappaport, “The Chemistry of the Cyano Group,” Interscience, New York,1970 or Patai and Rappaport, “The Chemistry of Functional Groups,” pt.2, Wiley, New York, 1983). The formula 7 or 8 nitrile is reduced with areducing agent such as borane-tetrahydrofuran complex, borane-methylsulfide complex, lithium aluminum hydride, or hydrogenation in thepresence of Raney nickel or a platinum or palladium catalyst in a proticsolvent such as methanol or ethanol at a temperature of about 0° C. toabout 50° C. The resulting formula 9 or 10 amine is converted to eitherthe formula 11 or 12 sulfonamide or amide by treatment (acylation) withan acid chloride or sulfonyl chloride in the presence of a weak basesuch as triethylamine, pyridine, or 4-methylmorpholine in an aproticsolvent such as methylene chloride or diethyl ether at a temperature ofabout −20° C. to about 50° C. Alternatively, coupling of amines offormulas 9 or 10 with carboxylic acids are conveniently carried out inan inert solvent such as dichloromethane or N,N-dimethylformamide (DMF)by a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or1,3-dicyclohexylcarbodiimide (DCC) in the presence of1-hydroxybenzotriazole hydrate (HOBT) to generate compounds of formula11 or 12. In the case where the amine is present as the hydrochloridesalt, it is preferable to add one equivalent of a suitable base such astriethylamine to the reaction mixture. Alternatively, the coupling canbe effected with a coupling reagent such asbenzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate(BOP) in an inert solvent such as methanol. Such coupling reactions aregenerally conducted at temperatures of about −30° C. to about 80° C.,preferably 0° C. to about 25° C. For a discussion of other conditionsused for coupling peptides see Houben-Weyl, Vol. XV, part II, E. Wunsch,Ed., George Theime Verlag, 1974, Stuttgart. Alkylation and if desired,deprotection, of the formula 11 or 12 compound as described in SCHEMES 1and 2 affords the corresponding acid formula 13 and 14 compound.

[0899] The formula 9 and 10 amines may also be prepared via reduction offormula 15 and 16 amides. The reduction can be achieved using reagentssuch as a borane-tetrahydrofuran complex, a borane-methyl sulfidecomplex, or diisobutyaluminum hydride in an aprotic solvent such astetrahydrofuran or diethyl ether at a temperature of about −78° C. toabout 60° C.

[0900] The formula 9 and 10 amines can also be obtained from thecorresponding nitro precursors by reduction of the nitro group usingreducing reagents such as zinc/HCl, hydrogenation in the presence ofRaney nickel, palladium, or platinum catalysts, and other reagents asdescribed by P. N. Rylander in “Hydrogenation Methods,” Academic Press,New York, 1985.

[0901] The description of, and preparation of other amines andalkylating agents useful for the above syntheses are described below inthe section entitled PREPARATIONS.

[0902] An alternative to the alkylation chemistry described above forthe preparation of Formula I compounds (wherein B is N and A, K, M and Qare as described in the Summary) involves reductive amination of anamine containing the necessary acidic functionality (suitably protected)with an aldehyde and is shown in SCHEME 5. Alternatively, the aldehydemay contain the acidic functionality for coupling with an amine.

[0903] The reductive amination is typically carried out with a reducingagent such as sodium cyanoborohydride or sodium triacetoxyborohydridepreferably at a pH of between 6 and 8. The reaction is normallyperformed in a protic solvent such as methanol or ethanol attemperatures of about −78° C. to about 40° C. (for a leading referencesee A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron Lett. 39, 31,5595-5598, 1990). Other conditions involve the use of titaniumisopropoxide and sodium cyanoborohydride (R. J. Mattson et al, J. Org.Chem. 1990, 55, 2552-4) or preformation of the imine under dehydratingconditions followed by reduction. The resulting formula 42, 42A amine,is transformed to the desired sulfonamide or amide by coupling with anacid chloride, sulfonyl chloride, or carboxylic acid as described inSCHEMES 3 and 4. If desired, hydrolysis provides the corresponding acid.

[0904] The description of and use of aldehydes useful in the aboveSCHEME 5 may be found in the PREPARATIONS section.

[0905] Alternatively, another method of preparing certain Formula Icompounds (i.e., formula 60 tetrazoles wherein B is N and A, K, M, and Qare as described above) is described in SCHEME 6. The starting formula 4sulfonamide or amide is alkylated with the appropriate alkyl halide orsulfonate (wherein X′ is halide or sulfonate), preferable a primary,secondary, benzylic, or allylic alkyl bromide, iodide, or sulfonate,which contains a nitrile to provide formula 59 compounds. The alkylationis achieved by treatment of the formula 59 compound with a base such assodium hydride, lithium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, potassium tert-butoxide, or potassiumcarbonate in an aprotic solvent such as dimethylformamide,dimethylformamide/benzene, or acetone. Alkylation occurs at atemperature of about −78° C. to about 100° C. Preferred conditions forconverting the resulting nitrile to the formula 60 tetrazole, involvetreatment with dibutyltin oxide and trimethylsilylazide, in toluene atreflux (S. J. Wittenberger and B. G. Donner, J. Org. Chem. 1993, 58,4139-4141, 1993). For a review of alternative preparations of tetrazolessee R. N. Butler, Tetrazoles, In Comprehensive Heterocyclic Chemistry;Potts, K. T. Ed.; Pergamon Press: Oxford, 1984, Vol. 5, pp 791-838.

[0906] Alternatively, another method of preparing certain Formula Icompounds (wherein B is N and A, Q and M are as described in theSummary) is described in SCHEME 7. Formula 46 esters can be preparedusing the procedures described earlier (see SCHEMES 1 and 2). SubsequentHeck coupling of this intermediate to an arylhalide (preferably an arylbromide or aryl iodide), an aryl triflate, or a ring system whichcontains a vinyl bromide, iodide, or triflate is accomplished with apalladium catalyst, such as palladium acetate ortetrakis(triphenylphosphine)palladium(0) in the presence of atrialkylamine, such as triethylamine. In some cases, a triarylphosphinemay be added to the reaction. The reaction is typically performed in anaprotic solvent such as dimethylformamide or acetonitrile at atemperature of about 0° C. to about 150° C. (see R. F. Heck in Comp.Org. Syn., Vol. 4, Ch. 4.3, p. 833 or Daves and Hallberg, Chem. Rev.1989, 89, 1433). If desired formula 47 compounds can be hydrolyzed tothe corresponding acid. Alternatively, the formula 47 compounds can behydrogenated and, if desired, further hydrolyzed to the correspondingformula 49 acid. Preferred conditions for hydrogenation involve the useof a palladium or platinum catalyst in an alcoholic solvent such asethanol or methanol at a temperature of about 0° C. to about 50° C. Incases where M represents a partially saturated ring system,hydrogenation will generate a saturated ring system.

[0907] Alternatively, another method of preparing certain Formula Icompounds (wherein B is N and A, Q, K and M are as described in theSummary and R is as described for SCHEMES 1 and 2) is described inSCHEME 8. Formula 51 compounds can be prepared as described in SCHEMES 1and 2 by alkylation of formula 5 compounds with an electrophile offormula 2 which contains the appropriate functionality on the ring M,for subsequent conversion to an aldehyde. For example, electrophiles offormula 2 (SCHEME 2) could contain a protected alcohol on the ring, M,which, after alkylation, can be deprotected and oxidized to thealdehyde, using reagents known to those skilled in the art, to generateformula 51 compounds. An alternative method is to alkylate with anelectrophile of formula 2 where M contains a vinyl group. Afteralkylation, oxidative cleavage of the double bond provides the desiredformula 51 aldehyde. The oxidative cleavage can be accomplished bytransforming the double bond to the 1,2-diol with catalytic osmiumtetroxide and N-methylmorpholine followed by oxidative cleavage to thealdehyde using sodium periodate. Alternatively, oxidative cleavage viaozonolysis followed by reduction using reagents such as methyl sulfide,triphenylphosphine, zinc/acetic acid, or thiourea, will generate thedesired formula 51 aldehyde. Addition of LMetal where LMetal representsany organometallic reagent such as an organolithium or Grignard reagentin an aprotic solvent such as diethyl ether or tetrahydrofuran at atemperature of about −78° C. to about 80° C., followed by hydrolysis ofthe ester as described above, provides the desired formula 50 compound.

[0908] Alternatively, another method of preparing certain Formula Icompounds (wherein B is N and A, K, and Q are as described in theSummary) is described in SCHEME 9. The appropriate formula 5 sulfonamideor amide is alkylated using the conditions described in SCHEMES 1 and 2with an electrophile which contains an aromatic bromide or iodide or aring system which contains a vinyl bromide or iodide (Ar₁) to provideformula 53 compounds. Suzuki-type coupling of the formula 53 compoundwith an aryl boronic acid (Ar₂) provides formula 53a compounds (for areview of the Suzuki reaction see A. R. Martin and Y. Yang in Acta Chem.Scand. 1993, 47, 221). The coupling reaction is achieved using about twoequivalents of a base, such as sodium carbonate, potassium carbonate,sodium hydroxide, thallium hydroxide, potassium phosphate, or sodiummethoxide, in the presence of a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0), palladium acetate, palladiumchloride, tris(dibenzylideneacetone)dipalladium(0) or[1,4-bis(diphenylphosphine)butane]palladium(0). The reaction may be runin aqueous alcoholic solvents (methanol or ethanol), aqueoustetrahydrofuran, aqueous acetone, aqueous glycol dimethyl ether, oraqueous benzene at temperatures ranging from about 0° C. to about 120°C. When Ar₁ represents a partially saturated ring, if appropriate,reduction of the ring to provide a saturated ring system may beperformed at this point. Conditions to accomplish this transformationinvolve hydrogenation in the presence of a catalyst such as palladium orplatinum in an alcoholic solvent (ethanol or methanol) and/or ethylacetate. Ester hydrolysis of formula 53a compounds, if desired, providesthe corresponding acid. The resulting acids may contain functionalgroups on either of the ring systems (Ar₁ or Ar₂) which can be modifiedusing methods known to those skilled in the art. Examples of suchmodifications are shown in SCHEME 10.

[0909] Formula 54 compounds which contain an aldehyde functional groupcan be prepared using methods described in SCHEMES 8 and 9. According toSCHEME 10, treatment of the formula 54 compound with an appropriateorganometallic reagent (LMetal), such as an organolithium or Grignardreagent, in an aprotic solvent such as diethyl ether or tetrahydrofuranat a temperature of about −78° C. to about 80° C., followed byhydrolysis of the ester, provides formula 56 compounds (wherein B is Nand A, Q and K are as described in the Summary and Ar₁ and Ar₂ are asdescribed in SCHEME 9). Alternatively, reduction of the aldehydefollowed by hydrolysis provides formula 55 compounds.

[0910] Alternatively, another method of preparing certain Formula Icompounds (i.e., formula 57 compounds wherein B is N and A, K, and Q areas described in the Summary and R is as described in SCHEMES 1 and 2 andaccordingly the corresponding acids) is described in SCHEME 11. Theformula 58 starting alcohol can be prepared using the methods describedin SCHEMES 1 and 2. Intermediate 58 is coupled with a variety of arylalcohols (M represents an aromatic ring) using Mitsonobu conditions (fora review see O. Mitsonobu, Synthesis, 1, 1981). Typically the couplingis achieved by addition of a coupling agent such as triphenylphosphineand diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate ininert solvents such as methylene chloride or tetrahydrofuran at atemperature of about 0° C. to about 80° C. If desired, subsequenthydrolysis yields the corresponding acid.

[0911] Alternatively, another method of preparing certain Formula Icompounds (i.e., formula 106 compounds wherein B is N and A, K, and Mare as described in the Summary and R is as described in SCHEMES 1 and 2and accordingly, the corresponding acids) is described in SCHEME 12. Aformula 102 compound is added to a formula 105 compound (wherein the Xis an aromatic ring such as a benzene ring or a thiophene ring) in thepresence of a Lewis acid such as titanium tetrachloride or a mineralacid such as hydrochloric acid. If desired the formula 106 ester can beconverted to the corresponding acid by hydrolysis or deprotection.

[0912] Alternatively, another method of preparing certain Formula Icompounds (i.e., formula 107 or 108 compounds wherein B is N and A, andQ are as described in the Summary and accordingly, the correspondingacids) is described in SCHEME 13. Formula 104 chloromethyl compounds aretreated with the appropriate substituted aromatic ring system, M, suchas 4-ethoxybenzene or thiophene in the presence of a Lewis acid such astitanium tetrachloride or a mineral acid such as hydrochloric acid in anaprotic solvent such as chloroform at a temperature of about 0° C. toabout 80° C. to yield the formula 107 compound which may subsequently behydrolyzed or deprotected as described above to yield the correspondingacid. Alternatively, formula 104 chloromethyl compounds can be treatedwith a Lewis acid such as titanium tetrachloride and an appropriatelysubstituted vinyl silane in an aprotic solvent such as methylenechloride at a temperature of about −50° C. to about 50° C. to giveformula 108 compounds which may subsequently be hydrolyzed ordeprotected as described above to yield the corresponding acid. Ifdesired, reduction of the double bond can be accomplished usingconditions described in SCHEME 7.

[0913] Alternatively, another method of preparing certain Formula Icompounds (i.e., formula 109 compounds, wherein B is N and A, Q, R and Mare as described above, and accordingly, the corresponding acids) isdescribed in SCHEME 14. Formula 104 chloromethyl compounds are treatedwith a Lewis acid such as titanium tetrachloride and an appropriatelysubstituted allyl silane in an aprotic solvent such as chloroform at atemperature of about 0° C. to about 80° C. to give formula 109 compoundswhich may subsequently be hydrolyzed or deprotected as described above.

[0914] Alternatively, another method of preparing certain Formula Icompounds (i.e., formula 112 compounds, wherein B is N and A, Q, R and Mare as described above, and accordingly, the corresponding acids) isdescribed in SCHEME 15. Formula 104 chloromethyl compounds are treatedwith a formula 111 sulfinic acid in the presence of a base such astriethylamine in an aprotic solvent such as chloroform at a temperatureof about −30° C. to about 50° C. to give formula 112 compounds which maysubsequently be hydrolyzed or deprotected as described above to yieldthe corresponding acid.

[0915] Formula I compounds (wherein B is C(H) and Q, M and K are asdescribed in the Summary, R′ is a small chain alkyl group, and R₁represents the alkyl groups on A as described in the Summary) can beprepared according to SCHEME 16. Formula 113 beta-ketoesters arealkylated sequentially with formula 114 compounds followed by alkylationof formula 116 compounds to give formula 117 compounds (J. Med. Chem.26, 1993, p335-41). Alkylations can be carried out in a suitable solventsuch as DMF, THF, ether, or benzene using an appropriate base such assodium hydride, LDA, or potassium carbonate at a temperature of about−78° C. to about 80° C. The resulting formula 117 disubstituted ketoesters are hydrolyzed and decarboxylated to give the correspondingformula 118 compound by using an aqueous base such as sodium hydroxideto hydrolyze the ester, followed by an acidic quench such as aqueoushydrochloric acid to effect decarboxylation.

[0916] Alternatively, Formula I compounds (wherein B is C(H) and Q, Mand K are as described in the Summary, R′ is as described above, and R₁represents the alkyl groups on A as described in the Summary) may beprepared according to SCHEME 17. Sequential alkylation of a malonatederivative of formula 119 provides the formula 121 dialkylated species.Deprotection of the ester group by treatment with a strong acid such asTFA or HCl in ethanol at a temperature of about −20° C. to about 50° C.leads to the formula 122 decarboxylated product. Conversion of the acidto an acid chloride using thionyl chloride or oxalyl chloride in anaprotic solvent at a temperature of about −78° C. to about 50° C. or toa Weinreb amide using methoxymethyl amine in the presence of a suitablecoupling agent such as DCC or DEC in an aprotic solvent at a temperatureof about −30° C. to about 50° C. provides formula 123 compounds. Formula123 are suitable substrates for addition of various organometallicspecies (e.g., grignard reagents, organo-cadmium reagents) which afterhydrolysis of the terminal ester provide the keto-acid compounds offormula 118.

[0917] Alternatively formula 118 compounds can be prepared using methodsdescribed previously (e.g. see SCHEMES 7, 8, 9, 10, and 11) where one orboth of the side chains are further functionalized after attachment.

PREPARATIONS

[0918] Amines, Amides and Sulfonamides

[0919] Certain amides or sulfonamides described by formulas 21, 22, and23 (wherein W and Z are as described in the Summary and X and M arearomatic or saturated ring systems may be prepared according to SCHEME18. Formula 25, 26 and 27 alkynyl amides or sulfonamides are prepared bycoupling a formula 24 alkynyl sulfonamide or amide to an aromatic orvinyl halide, preferably an aromatic or vinyl bromide or iodide (whereinW and Z are as defined above and where X and M represent an aromaticring or a partially saturated ring system). The coupling is typicallyaccomplished in the presence of copper iodide, a palladium catalyst,such as palladium chloride, bis(triphenylphosphine)palladium dichloride,or tetrakis(triphenylphosphine)palladium(0), and an amine such astriethylamine, diisopropylamine, or butylamine in an aprotic solventsuch as acetonitrile at a temperature of about 0° C. to about 100° C.The resulting formula 25, 26 and 27 alkynes can be converted to thecorresponding formula 21, 22 or 23 alkanes, via hydrogenation in thepresence of a palladium or platinum catalyst and in solvents such asmethanol, ethanol, and/or ethyl acetate at a temperature of about 0° C.to about 50° C. Alternatively, one can convert the alkyne to thecis-alkene using the Lindlar catalyst (Pd—CaCO₃—PbO). In the case whereM represents a partially saturated ring system, hydrogenation willconvert M to a fully saturated ring system. Alkylation and deprotectionas described in SCHEMES 1 and 2 affords the corresponding Formula Icompounds.

[0920] According to SCHEME 19 formula 33 compounds (wherein A and X areas described in the Summary) can be prepared from a suitable formula 32amine (e.g., methoxyarylalkylamine). Formula 32 amines are commerciallyavailable or can be prepared by methods known to those skilled in theart (for example, see SCHEME 4) and are converted to formula 31sulfonamides or amides using methods, for example, described in SCHEME 3and 4. The resulting formula 31 aromatic methyl ether is deprotectedwith reagents such as boron tribromide, pyridinium hydrochloride,hydrogen bromide/acetic acid, or other reagents as described inProtecting Groups in Organic Synthesis, Second Edition, T. W. Greene andP. G. M. Wuts, John Wiley and Sons, Inc., 1991. Alkylation with abromoalkylester using a mild base such as potassium carbonate in anaprotic solvent such as dimethylformamide or acetone at a temperature ofabout 0° C. to about 100° C. generates the desired formula 33 amide orsulfonamide.

[0921] Alkylating Agents

[0922] Numerous methods exist for the synthesis of the desiredalkylating agents used in the above procedures and are known to thoseskilled in the art (see “The Chemistry of the Carbon-Halogen Bond,” Ed.S. Patai, J. Wiley, New York, 1973 and “The Chemistry of Halides,Pseudo-Halides, and Azides,” Eds. S. Patai and Z. Rappaport, J. Wiley,New York, 1983). Some examples are shown in SCHEMES 20-26. As shown inSCHEME 20, tolyl or allylic substrates can be converted via halogenationto benzylic or allylic bromides (wherein M, X, W and Z are as describedin the Summary). This reaction is typically performed withN-bromosuccinimide (NBS) in the presence of a radical initiator such asAIBN or a peroxide, preferably benzoyl peroxide. Alternatively, thereaction can be initiated with light. The reaction is done in an inertsolvent such as carbon tetrachloride or chloroform at a temperature ofabout 50° C. to about 100° C.

[0923] SCHEME 21 demonstrates the synthesis of alkylating agents usefulfor preparing Formula I compounds where M represents a biaryl or arylcyclic group. Suzuki-type coupling of an aryl iodide or bromide or aring system containing a vinyl bromide or iodide (Ar₂) with a methylarylboronic acid (Ar₁) using the conditions described in SCHEME 9 providesformula 34 compounds. In the case where a vinyl bromide or iodide isused, formula 34 compounds can be reduced to generate a fully saturatedring. The reduction is accomplished by hydrogenation in the presence ofpalladium or platinum catalysts typically in protic solvents (methanolor ethanol), tetrahydrofuran, or ethyl acetate. Halogenation of themethyl group using reagents and conditions as described in SCHEME 20provides formula 35 alkylating agents.

[0924] Another common method for accessing alkyl halides is byhalogenation of an alcohol or an alcohol derivative. Alcohols areobtained from commercial sources or can be prepared using methods knownto those skilled in the art. For example, in SCHEME 22, a carboxylicacid or ester is reduced to the alcohol using reagents such as sodiumborohydride, lithium aluminum hydride, borane-tetrahydrofuran complex,borane-methyl sulfide complex, etc. The corresponding alkyl chloridesare typically prepared from the alcohols with reagents such as hydrogenchloride, thionyl chloride, phosphorous pentachloride, phosphorousoxychloride, or triphenylphosphine/carbon tetrachloride. For thepreparation of alkyl bromides, the alcohol is commonly treated withreagents such as hydrogen bromide, phosphorous tribromide,triphenylphosphine/bromine, or carbonyidiimidazole/allyl bromide(Kamijo, T., Harada, H., Iizuka, K. Chem. Pharm. Bull. 1983, 38, 4189).To access alkyl iodides, one typically reacts the alcohol with reagentssuch as triphenylphosphine/iodine/imidazole or hydogen iodide. Alkylchlorides can be converted to the more reactive alkyl bromides or alkyliodides by treatment with an inorganic salt such as sodium bromide,lithium bromide, sodium iodide, or potassium iodide in solvents such asacetone or methyl ethyl ketone. Alkyl sulfonates can also be used aselectrophiles or can be converted to alkyl halides. Sulfonates areprepared from the alcohol using a mild base such as triethylamine orpyridine and a sulfonyl chloride in an inert solvent such a methylenechloride or diethyl ether. Conversion to the halide is accomplished bytreatment with an inorganic halide (sodium iodide, sodium bromide,potassium iodide, potassium bromide, lithium chloride, lithium bromide,etc) or a tetrabutylammonium halide.

[0925] Cinnamic acids or esters are commonly available from commercialsources and can by converted to formula 37 or 38 alkylating agents asfollows (see SCHEME 23). The cinnamic acid or ester derivatives arereduced by hydrogenation in the presence of palladium or platinumcatalysts typically in protic solvents (e.g., methanol or ethanol),tetrahydrofuran, or ethyl acetate. Reduction and conversion to the alkylhalide or sulfonate as described in SCHEME 22 provides formula 38. Whereappropriate, the cinnamic acids or esters are converted directly toformula 39 alcohols by treatment with reagents such as lithium aluminumhydride in inert solvents such as tetrahydrofuran and diethyl ether.Alternatively, the cinnamic acid or ester can be reduced to the formula40 allylic alcohol using reagents such as lithium aluminumhydride/aluminum chloride, diisobutylaluminum hydride, or lithiumborohydride. Conversion to the allylic halide or sulfonate as describedin SCHEME 22 provides formula 37 reagents.

[0926] The preparation of formula 41 alkylating agents (wherein W and Mare as described in the Summary above) are described in SCHEME 24.Formula 42 compounds are alkylated with a variety of bases the choice ofwhich is dependent on the nature of W and M. Some preferred bases aresodium hydroxide, sodium hydride, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide andpotassium tert-butoxide, etc. Treatment of the resulting anion with avariety of dialkylhalides generates the desired formula 41 alkylatingagents. For the preparation of compounds where W represents an oxygenand M is an aromatic ring, the preferred conditions involve formation ofthe alkoxide anion with sodium hydroxide followed by addition of adihaloalkane, e.g. dibromoalkane. The reaction is normally performed inwater at about 75° C. to about 125° C.

[0927] Aldehydes useful for the chemistry described in SCHEME 5 areavailable from commercial sources or can be prepared from availableintermediates using methods known to those skilled in the art. SCHEME 25demonstrates an exemplary method used to prepare formula 43 hydroxyaldehydes (where M in SCHEME 5 contains a hydroxy substituted alkylgroup). Treatment of a dialdehyde, where one of the aldehydes isprotected as a formula 44 acetal (wherein the OR groups are conventionalsubstituents used in an acetal protecting group), with an organometallicreagent (LMetal), preferably an organolithium or Grignard reagent, in aninert solvent such as tetrahydrofuran or diethyl ether, provides formula45 compounds. Subsequent acetal hydrolysis under mildly acidicconditions, e.g. dilute hydrogen chloride, Amberlyst-15 resin, silicagel, or other reagents as described in “Protecting Groups in OrganicSynthesis,” Second Edition, T. W. Greene and P. G. M. Wuts, John Wileyand Sons, Inc., 1991 provides the desired formula 43 hydroxy aldehydes.

[0928] Chloromethyl Intermediates

[0929] Intermediate chloromethyl compounds can be prepared as describedin SCHEMES 26 and 27. In general, the appropriate formula 101 or 103sulfonamide or carboxamide is treated with a formaldehyde equivalentsuch as paraformaldehyde in an inert organic solvent such as methylenechloride or chloroform with a suitable catalyst such as HCl, zincchloride or trimethylsilyl chloride at temperatures ranging from about0° C. to about 60° C. to give the formula 102 and 104 chloromethylderivatives, respectively.

[0930] Those skilled in the art will recognize that anti-resorptiveagents (for example progestins polyphosphonates, bisphosphonate(s),estrogen agonists/antagonists, estrogen, estrogen/progestincombinations, Premarin, estrone, estriol or 17α- or 17β-ethynylestradiol) may be used in conjunction with the compounds of thisinvention.

[0931] Exemplary progestins are available from commercial sources andinclude: algestone acetophenide, altrenogest, amadinone acetate,anagestone acetate, chlormadinone acetate, cingestol, clogestoneacetate, clomegestone acetate, delmadinone acetate, desogestrel,dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate,etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonoronecaproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate,levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate,melengestrol acetate, methynodiol diacetate, norethindrone,norethindrone acetate, norethynodrel, norgestimate, norgestomet,norgestrel, oxogestone phenpropionate, progesterone, quingestanolacetate, quingestrone, and tigestol.

[0932] Preferred progestins are medroxyprogestrone, norethindrone andnorethynodrel.

[0933] Exemplary bone resorption inhibiting polyphosphonates includepolyphosphonates of the type disclosed in U.S. Pat. No. 3,683,080,granted Aug. 8, 1972, the disclosures of which are incorporated hereinby reference. Preferred polyphosphonates are geminal diphosphonates(also referred to as bis-phosphonates). Tiludronate disodium is anespecially preferred polyphosphonate. Ibandronic acid is an especiallypreferred polyphosphonate. Alendronate is an especially preferredpolyphosphonate. Other preferred polyphosphonates are6-amino-1-hydroxy-hexylidene-bisphosphonic acid and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. Thepolyphosphonates may be administered in the form of the acid, or of asoluble alkali metal salt or alkaline earth metal salt. Hydrolyzableesters of the polyphosphonates are likewise included. Specific examplesinclude ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonicacid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichlorodiphosphonic acid, methane hydroxy diphosphonic acid,ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonicacid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-3-3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylamino methane diphosphonic acid,N,N-dimethylamino methane diphosphonicacid, N(2-hyroxyethyl) amino methane diphosphonic acid,butane-4-amino-1-hydroxy-1,1-diphosphonic acid,pentane-5-amino-1-hydroxy-1,1-diphosphonic acid,hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceuticallyacceptable esters and salts thereof.

[0934] In particular, the compounds of this invention may be combinedwith a mammalian estrogen agonist/antagonist. Any estrogenagonist/antagonist may be used as the second compound of this invention.The term estrogen agonist/antagonist refers to compounds which bind withthe estrogen receptor, inhibit bone turnover and prevent bone loss. Inparticular, estrogen agonists are herein defined as chemical compoundscapable of binding to the estrogen receptor sites in mammalian tissue,and mimicking the actions of estrogen in one or more tissue. Estrogenantagonists are herein defined as chemical compounds capable of bindingto the estrogen receptor sites in mammalian tissue, and blocking theactions of estrogen in one or more tissues. Such activities are readilydetermined by those skilled in the art according to standard assaysincluding estrogen receptor binding assays, standard bonehistomorphometric and densitometer methods, (Eriksen E. F. et al., BoneHistomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J.et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below.

[0935] A preferred estrogen agonist/antagonist is droloxifene: (phenol,3-[1-[4[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl]-, (E)-) andassociated compounds which are disclosed in U.S. Pat. No. 5,047,431 (thedisclosure of which is hereby incorporated by reference).

[0936] Another preferred estrogen agonist/antagonist is tamoxifen:(ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl, (Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and associated compoundswhich are disclosed in U.S. Pat. No. 4,536,516 (the disclosure of whichis hereby incorporated by reference).

[0937] Another related compound is 4-hydroxy tamoxifen which isdisclosed in U.S. Pat. No. 4,623,660 (the disclosure of which is herebyincorporated by reference).

[0938] A preferred estrogen agonist/antagonist is raloxifene:(methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-,hydrochloride)which is disclosed in U.S. Pat. No. 4,418,068 (the disclosure of whichis hereby incorporated by reference).

[0939] Another preferred estrogen agonist/antagonist is toremifene:(ethanamine,2-[4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)—,2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in U.S.Pat. No. 4,996,225 (the disclosure of which is hereby incorporated byreference).

[0940] Another preferred estrogen agonist/antagonist is centchroman:1-[2-[[4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy]-ethyl]-pyrrolidine, which isdisclosed in U.S. Pat. No. 3,822,287 (the disclosure of which is herebyincorporated by reference). Also preferred is levormeloxifene.

[0941] Another preferred estrogen agonist/antagonist is idoxifene:pyrrolidine, 1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-butenyl]phenoxy]ethyl]which is disclosed in U.S. Pat. No. 4,839,155 (the disclosure of whichis hereby incorporated by reference).

[0942] Another preferred estrogen agonist/antagonist is6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-olwhich is disclosed in U.S. Pat. No. 5,484,795 the disclosure of which ishereby incorporated by reference.

[0943] Another preferred estrogen agonist/antagonist is{4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanonewhich is disclosed, along with methods of preparation, in PCTpublication no. WO 95/10513 assigned to Pfizer Inc.

[0944] Another preferred estrogen agonist/antagonist is GW5638:3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid; see Wilson, T. M.and coworkers in Endrocrinology 1997, 138, 9, 3901-3911.

[0945] Other preferred estrogen agonist/antagonists include compounds asdescribed in commonly assigned U.S. Pat. No. 5,552,412 the disclosure ofwhich is hereby incorporated by reference. Especially preferred compundsdescribed therein are:

[0946]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0947](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0948]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[0949]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[0950]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[0951]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;and

[0952]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

[0953] Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814 (the disclosure of which is hereby incorporated by reference).U.S. Pat. No. 4,133,814 discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

[0954] Those skilled in the art will recognize that other bone anabolicagents (bone mass augmenting agents) may be used in conjunction with thecompounds of this invention. A bone mass augmenting agent is a compoundthat augments bone mass to a level which is above the bone fracturethreshold (as detailed in the World Health Organization Study WorldHealth Organization, “Assessment of Fracture Risk and its Application toScreening for Postmenopausal Osteoporosis (1994). Report of a WHO StudyGroup. World Health Organization Technical Series 843”).

[0955] Any prostaglandin, or prostaglandin agonist/antagonist may beused as the second compound of this invention (this would includeutilizing two different compounds of Formula I of this inventon). Thoseskilled in the art will recognize that IGF-1, with or without IGFbinding protein 3, sodium fluoride, parathyroid hormone (PTH), activefragments of parathyroid hormone, growth hormone or growth hormonesecretagogues may also be used. The following paragraphs describeexemplary second compounds of this invention in greater detail.

[0956] Any prostaglandin may be used as the second compound of thisinvention. The term prostaglandin refers to compounds which are analogsof the natural prostaglandins PGD₁, PGD₂, PGE₂, PGE₁ and PGF₂ which areuseful in the treatment of osteoporosis. These compounds bind to theprostaglandin receptors. Such binding is readily determined by thoseskilled in the art according to standard assays (e.g., An S. et al.,Cloning and Expression of the EP₂ Subtype of Human Receptors forProstaglandin E₂, Biochemical and Biophysical Research Communications,1993, 197(1):263-270).

[0957] Prostaglandins are alicyclic compounds related to the basiccompound prostanoic acid. The carbon atoms of the basic prostaglandinare numbered sequentially from the carboxylic carbon atom through thecyclopentyl ring to the terminal carbon atom on the adjacent side chain.Normally the adjacent side chains are in the trans orientation. Thepresence of an oxo group at C-9 of the cyclopentyl moiety is indicativeof a prostaglandin within the E class while PGE₂ contains a transunsaturated double bond at the C₁₃-C₁₄ and a cis double bond at theC₅-C₆ position.

[0958] A variety of prostaglandins are described and referenced below,however, other prostaglandins will be known to those skilled in the art.Exemplary prostaglandins are disclosed in U.S. Pat. Nos. 4,171,331 and3,927,197 (the disclosures of which are hereby incorporated byreference).

[0959] Norrdin et al., The Role of Prostaglandins in Bone In Vivo,(Prostaglandins Leukotriene Essential Fatty Acids 41, 139-150, 1990) isa review of bone anabolic prostaglandins. Jee and Ma, The In VivoAnabolic Actions of Prostaglandins in Bone. (Bone, 21: 297-304) is arecent review of prostaglandins' bone anabolic action.

[0960] Any prostaglandin agonist/antagonist may be used as the secondcompound of this invention. The term prostaglandin agonist/antagonistrefers to compounds which bind to prostaglandin receptors (e.g., J. W.Regan et al., Cloning of a Novel Human Prostaglandin Receptor withCharacteristics of the Pharmacologically Defined EP₂ Subtype, MolecularPharmacology, 46: 213-220, 1994.) and mimic the action of prostaglandinin vivo (e.g., stimulate bone formation and increase bone mass andstrength). Such actions are readily determined by those skilled in theart according to standard assays (Eriksen E. F. et al., BoneHistomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J.et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below, however, otherprostaglandin agonists/antagonists will be known to those skilled in theart. Exemplary prostaglandin agonists/antagonists are disclosed asfollows.

[0961] Commonly assigned U.S. Pat. No. 3,932,389 (the disclosure ofwhich is hereby incorporated by reference) discloses2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-omega-pentanorprostaglandinsuseful for bone formation activity.

[0962] Commonly assigned U.S. Pat. No. 4,018,892 (the disclosure ofwhich is hereby incorporated by reference) discloses16-aryl-13,14-dihydro-PGE₂ p-biphenyl esters useful for bone formationactivity.

[0963] Commonly assigned U.S. Pat. No. 4,219,483 (the disclosure ofwhich is hereby incorporated by reference) discloses2,3,6-substituted-4-pyrones useful for bone formation activity.

[0964] Commonly assigned U.S. Pat. No. 4,132,847 (the disclosure ofwhich is hereby incorporated by reference) discloses2,3,6-substituted-4-pyrones useful for bone formation activity.

[0965] U.S. Pat. No. 4,000,309 (the disclosure of which is herebyincorporated by reference) discloses 16-aryl-13,14-dihydro-PGE₂p-biphenyl esters useful for bone formation activity.

[0966] U.S. Pat. No. 3,982,016 (the disclosure of which is herebyincorporated by reference) discloses 16-aryl-13,14-dihydro-PGE₂p-biphenyl esters useful for bone formation activity.

[0967] U.S. Pat. No. 4,621,100 (the disclosure of which is herebyincorporated by reference) discloses substituted cyclopentanes usefulfor bone formation activity.

[0968] U.S. Pat. No. 5,216,183 (the disclosure of which is herebyincorporated by reference) discloses cyclopentanones useful for boneformation activity.

[0969] Sodium fluoride may be used as the second compound of thisinvention. The term sodium fluoride refers to sodium fluoride in all itsforms (e.g., slow release sodium fluoride, sustained release sodiumfluoride). Sustained release sodium fluoride is disclosed in U.S. Pat.No. 4,904,478, the disclosure of which is hereby incorporated byreference. The activity of sodium fluoride is readily determined bythose skilled in the art according to biological protocols (e.g., seeEriksen E. F. et al., Bone Histomorphometry, Raven Press, New York,1994, pages 1-74; Grier S. J. et. al., The Use of Dual-Energy X-RayAbsorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H. W.and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-RayAbsorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994,pages 1-296).

[0970] Any parathyroid hormone (PTH) may be used as the second compoundof this invention. The term parathyroid hormone refers to parathyroidhormone, fragments or metabolites thereof and structural analogs thereofwhich can stimulate bone formation and increase bone mass. Also includedare parathyroid hormone related peptides and active fragments andanalogues of parathyroid related peptides see WO 94/01460. Suchfunctional activity is readily determined by those skilled in the artaccording to standard assays (e.g., see Eriksen E. F. et al., BoneHistomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J.et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below, however, other parathyroidhormones will be known to those skilled in the art. Exemplaryparathyroid hormones are disclosed in the following references.

[0971] “Human Parathyroid Peptide Treatment of Vertebral Osteoporosis”,Osteoporosis Int., 3, (Supp 1):199-203.

[0972] “PTH 1-34 Treatment of Osteoporosis with Added HormoneReplacement Therapy: Biochemical, Kinetic and Histological Responses”Osteoporosis Int. 1:162-170.

[0973] Any growth hormone or growth hormone secretagogue may be used asthe second compound of this invention. The term growth hormonesecretagogue refers to compounds which stimulate the release of growthhormone or mimic the action of growth hormone (e.g., increase boneformation leading to increased bone mass). Such actions are readilydetermined by those skilled in the art according to standard assays. Avariety of these compounds are included in the following published PCTpatent applications: WO 95/14666; WO 95/13069; WO 94/19367; WO 94/13696;and WO 95/34311. However, other growth hormone or growth hormonesecretagogues will be known to those skilled in the art.

[0974] In particular a preferred growth hormone secretagogue isN-[1(R)-[1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4′-piperidin]-1′-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide:MK-677.

[0975] Other preferred growth hormone secretagogues include

[0976]2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideor its L-tartaric acid salt;

[0977]2-Amino-N-{1-(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}isobutyramide;and

[0978]2-Amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)benzyloxymethyl-2-oxo-ethyl]isobutyramide.

[0979]2-Amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide

[0980] Some of the preparation methods useful for the preparation of thecompounds described herein may require protection of remotefunctionality (e.g., primary amine, secondary amine, carboxyl in FormulaI precursors). The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. The need for such protection is readily determined by oneskilled in the art. The use of such protection/deprotection methods isalso within the skill in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

[0981] The starting materials and reagents for the above describedcompounds, are also readily available or can be easily synthesized bythose skilled in the art using conventional methods of organicsynthesis. For example, many of the compounds used therein, are relatedto, or are derived from compounds found in nature, in which there is alarge scientific interest and commercial need, and accordingly many suchcompounds are commercially available or are reported in the literatureor are easily prepared from other commonly available substances bymethods which are reported in the literature. Such compounds include,for example, prostaglandins.

[0982] Some of the compounds of this invention have asymmetric carbonatoms and therefore are enantiomers or diastereomers. Diasteromericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods known per se.,for example, by chromatography and/or fractional crystallization.Enantiomers can be separated by converting the enantiomeric mixture intoa diasteromeric mixture by reaction with an appropriate optically activecompound (e.g., alcohol), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereomers to the correspondingpure enantiomers. All such isomers, including diastereomers, enantiomersand mixtures thereof are considered as part of this invention. Also,some of the compounds of this invention are atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.

[0983] Many of the compounds of this invention are acidic and they forma salt with a pharmaceutically acceptable cation. Some of the compoundsof this invention are basic and they form a salt with a pharmaceuticallyacceptable anion. All such salts are within the scope of this inventionand they can be prepared by conventional methods. For example, they canbe prepared simply by contacting the acidic and basic entities, usuallyin a stoichiometric ratio, in either an aqueous, non-aqueous orpartially aqueous medium, as appropriate. The salts are recovered eitherby filtration, by precipitation with a non-solvent followed byfiltration, by evaporation of the solvent, or, in the case of aqueoussolutions, by lyophilization, as appropriate.

[0984] In addition, when the compounds of this invention form hydratesor solvates they are also within the scope of the invention.

[0985] The compounds of this invention are all adapted to therapeuticuse as agents that stimulate bone formation and increase bone mass inmammals, particularly humans. Since bone formation is closely related tothe development of osteoporosis and bone related disorders, thesecompounds, by virtue of their action on bone, prevent, arrest and/orregress osteoporosis.

[0986] The utility of the compounds of the present invention as medicalagents in the treatment of conditions which present with low bone mass(e.g., osteoporosis) in mammals (e.g. humans, particularly the female)is demonstrated by the activity of the compounds of this invention inconventional assays, including the in vivo assay, a receptor bindingassay, the Cyclic AMP assay and the Fracture healing assay (all of whichare described below). The in vivo assay (with appropriate modificationswithin the skill in the art) may be used to determine the activity ofother anabolic agents as well as the prostaglandin agonists of thisinvention. The estrogen agonist/antagonist protocol may be used todetermine the activity of estrogen agonists/antagonists in particularand also other anti-resorptive agents (with appropriate modificationswithin the skill in the art). The combination and sequential treatmentprotocol described below is useful for demonstrating the utility of thecombinations of the anabolic agents (e.g., the compounds of thisinvention) and anti-resorptive agents (e.g., estrogenagonists/antagonists) described herein. Such assays also provide a meanswhereby the activities of the compounds of this invention (or the otheranabolic agents and anti-resorptive agents described herein) can becompared to each other and with the activities of other known compounds.The results of these comparisons are useful for determining dosagelevels in mammals, including humans, for the treatment of such diseases.

[0987] Anabolic Agent In Vivo Assay

[0988] The activity of anabolic bone agents in stimulating boneformation and increasing bone mass can be tested in intact male orfemale rats, sex hormone deficient male (orchidectomy) or female(ovariectomy) rats.

[0989] Male or female rats at different ages (such as 3 months of age)can be used in the study. The rats are either intact or castrated(ovariectomized or orchidectomized), and subcutaneously injected orgavaged with prostaglandin agonists at different doses (such as 1, 3, or10 mg/kg/day) for 30 days. In the castrated rats, treatment is startedat the next day after surgery (for the purpose of preventing bone loss)or at the time bone loss has already occured (for the purpose ofrestoring bone mass). During the study, all rats are allowed free accessto water and a pelleted commercial diet (Teklad Rodent Diet #8064,Harlan Teklad, Madison, Wis.) containing 1.46% calcium, 0.99% phosphorusand 4.96 IU/g of Vit.D₃. All rats are given subcutaneous injections of10 mg/kg calcein on days 12 and 2 before sacrifice. The rats aresacrificed. The following endpoints are determined:

[0990] Femoral Bone Mineral Measurements:

[0991] The right femur from each rat is removed at autopsy and scannedusing dual energy x-ray absorptiometry (DXA, QDR 1000/W, Hologic Inc.,Waltham, Mass.) equipped with “Regional High Resolution Scan” software(Hologic Inc., Waltham, Mass.). The scan field size is 5.08×1.902 cm,resolution is 0.0254×0.0127 cm and scan speed is 7.25 mm/second. Thefemoral scan images are analyzed and bone area, bone mineral content(BMC), and bone mineral density (BMD) of whole femora (WF), distalfemoral metaphyses (DFM), femoral shaft (FS), and proximal femora (PF)are determined.

[0992] Tibial Bone Histomorphometric Analyses:

[0993] The right tibia is removed at autopsy, dissected free of muscle,and cut into three parts. The proximal tibia and the tibial shaft arefixed in 70% ethanol, dehydrated in graded concentrations of ethanol,defatted in acetone, then embedded in methyl methacrylate (EastmanOrganic Chemicals, Rochester, N.Y.).

[0994] Frontal sections of proximal tibial metaphyses at 4 and 10 μmthickness are cut using Reichert-Jung Polycut S microtome. The 4 μmsections are stained with modified Masson's Trichrome stain while the 10μm sections remained unstained. One 4 μm and one 10 μm sections fromeach rat are used for cancellous bone histomorphometry.

[0995] Cross sections of tibial shaft at 10 μm thickness are cut usingReichert-Jung Polycut S microtome. These sections are using for corticalbone histomorphometric analysis.

[0996] Cancellous bone histomorphometry: A Bioquant OS/2histomorphometry system (R&M biometrics, Inc., Nashville, Tenn.) is usedfor the static and dynamic histomorphometric measurements of thesecondary spongiosa of the proximal tibial metaphyses between 1.2 and3.6 mm distal to the growth plate-epiphyseal junction. The first 1.2 mmof the tibial metaphyseal region needs to be omitted in order torestrict measurements to the secondary spongiosa. The 4 μm sections areused to determine indices related to bone volume, bone structure, andbone resorption, while the 10 μm sections are used to determine indicesrelated to bone formation and bone turnover.

[0997] I) Measurements and calculations related to trabecular bonevolume and structure: (1) Total metaphyseal area (TV, mm²): metaphysealarea between 1.2 and 3.6 mm distal to the growth plate-epiphysealjunction. (2) Trabecular bone area (BV, mm²): total area of trabeculaewithin TV. (3) Trabecular bone perimeter (BS, mm): the length of totalperimeter of trabeculae. (4) Trabecular bone volume (BV/TV, %):BV/TV×100. (5) Trabecular bone number (TBN, #/mm): 1.199/2×BS/TV. (6)Trabecular bone thickness (TBT, μm): (2000/1.199)×(BV/BS). (7)Trabecular bone separation (TBS, μm): (2000×1.199)×(TV−BV).

[0998] II) Measurements and calculations related to bone resorption: (1)Osteoclast number (OCN, #): total number of osteoclast within totalmetaphyseal area. (2) Osteoclast perimeter (OCP, mm): length oftrabecular perimeter covered by osteoclast. (3) Osteoclast number/mm(OCN/mm, #/mm): OCN/BS. (4) Percent osteoclast perimeter (% OCP, %):OCP/BS×100.

[0999] III) Measurements and calculations related to bone formation andturnover: (1) Single-calcein labeled perimeter (SLS, mm): total lengthof trabecular perimeter labeled with one calcein label. (2)Double-calcein labeled perimeter (DLS, mm): total length of trabecularperimeter labeled with two calcein labels. (3) Inter-labeled width (ILW,μm): average distance between two calcein labels. (4) Percentmineralizing perimeter (PMS, %): (SLS/2+DLS)/BS×100. (5) Mineralapposition rate (MAR, μm/day): ILW/label interval. (6) Bone formationrate/surface ref. (BFR/BS, μm²/d/μm): (SLS/2+DLS)×MAR/BS. (7) Boneturnover rate (BTR, %/y): (SLS/2+DLS)×MAR/BV×100.

[1000] Cortical bone histomorphometry: A Bioquant OS/2 histomorphometrysystem (R&M biometrics, Inc., Nashville, Tenn.) is used for the staticand dynamic histomorphometric measurements of tibial shaft corticalbone. Total tissue area, marrow cavity area, periosteal perimeter,endocortical perimeter, single labeled perimeter, double labeledperimeter, and interlabeled width on both periosteal and endocorticalsurface are measured, and cortical bone area (total tissue area−marrowcavity area), percent cortical bone area (cortical area/total tissuearea×100), percent marrow area (marrow cavity area/total tissuearea×100), periosteal and endocortical percent labeled perimeter[(single labeled perimeter/2+double labeled perimeter)/totalperimeter×100], mineral apposition rate (interlabeled width/intervals),and bone formation rate [mineral apposition rate×[(single labeledperimeter/2+double labeled perimeter)/total perimeter] are calculated.

[1001] Statistics

[1002] Statistics can be calculated using StatView 4.0 packages (AbacusConcepts, Inc., Berkeley, Calif.). The analysis of variance (ANOVA) testfollowed by Fisher's PLSD are used to compare the differences betweengroups.

[1003] Determination of cAMP Elevation in 293-S Cell Lines StablyOverexpressing Recombinant Human EP2 and EP4 Receptors.

[1004] cDNAs representing the complete open reading frames of the humanEP2 and EP4 receptors are generated by reverse transcriptase polymerasechain reaction using oligonucleotide primers based on publishedsequences (1, 2) and RNA from primary human kidney cells (EP2) orprimary human lung cells (EP4) as templates. cDNAs are cloned into themultiple cloning site of pcDNA3 (Invitrogen) and used to transfect 293-Shuman embryonic kidney cells via calcium phosphate co-precipitation.G418-resistent colonies are expanded and tested for specific [3-H]PGE2binding. Transfectants demonstrating high levels of specific [3-H]PGE2binding are further characterized by scatchard analysis to determineBmax and Kds for PGE2. The lines selected for compound screening haveapproximately 338,400 receptors per cell and a Kd=12 nM for PGE2 (EP2),and approximately 256,400 receptors per cell and a Kd=2.9 nM for PGE2(EP4). Constituitive expression of both receptors in parental 293-Scells is negligible. Cells are maintained in RPMI supplemented withfetal bovine serum (10% final) and G418 (700 ug/ml final).

[1005] cAMP responses in the 293-S/EP2 and 293-S/EP4 lines aredetermined by detaching cells from culture flasks in 1 ml of Ca++ andMg++ deficient PBS via vigorous pounding, adding serum-free RPMI to afinal concentration of 1×10⁶ cells/ml, and adding3-isobutyl-1-methylxanthine (IBMX) to a final concentration of 1 mM. Onemilliliter of cell suspension is immediately aliquoted into individual 2ml screwcap microcentrifuge and incubated for 10 minutes, uncovered, at37° C., 5% CO₂,95% relative humdity. The compound to be tested is thenadded to cells at 1:100 dilutions such that final DMSO or ethanolconcentrations is 1%. Immediately after adding compound, the tubes arecovered, mixed by inverting two times, and incubated at 37° C. for 12minutes. Samples are then Jysed by incubation at 100° C. for 10 minutesand immediately cooled on ice for 5 minutes. Cellular debris is pelletedby centrifugation at 1000×g for 5 minutes, and cleared lysates aretransferred to fresh tubes. cAMP concentrations are determined using acommercially available cAMP radioimmunoassay kit (NEK-033, NEN/DuPont)after diluting cleared lysates 1:10 in cAMP RIA assay buffer. Typically,one treats cells with 6-8 concentrations of the compound to be tested in1 log increments. EC50 calculations are performed on a Hewlett Packard32SII hand-held calculator using linear regression analysis on thelinear portion of the dose response curves.

[1006] References

[1007] 1. Regan, J. W. Bailey, T. J. Pepperl, D. J. Pierce, K. L.Bogardus,A. M. Donello, J. E. Fairbairn, C. E. Kedzie, K. M. Woodward,D. F. and Gil, D. W. 1994 Cloning of a Novel Human ProstaglandinReceptor with Characteristics of the Pharmaclogically Defined EP₂Subtype. Mol. Pharmacology 46:213-220.

[1008] 2. Bastien, L., Sawyer, N., Grygorczyk, R., Metters, K., andAdam, M. 1994 Cloning, Functional Expression, and Characterization ofthe Human Prostaglandin E2 Receptor EP2 Subtype. J. Biol. Chem. Vol 269,16:11873-11877.

[1009] Assay for Binding to Prostaglandin E2 Receptors

[1010] Membrane Preparation: All operations are performed at 4° C.Transfected cells expressing prostaglandin E2 type 1 receptors (EP1),type 2 (EP2), type 3 (EP3) or type 4 (EP4) receptors are harvested andsuspended to 2 million cells per ml in Buffer A [50 mM Tris-HCl (pH7.4), 10 mM MgCl₂, 1 mM EDTA, 1 mM Pefabloc peptide, (Sigma, St. Louis,Mo.), 10 uM Phosporamidon peptide, (Sigma, St. Louis, Mo.), 1 uMPepstatin A peptide, (Sigma, St. Louis, Mo.), 10 uM Elastatinal peptide,(Sigma, St. Louis, Mo.), 100 uM Antipain peptide, (Sigma, St. Louis,Mo.)]. These are lysed by sonification with a Branson Sonifier (Model#250, Branson Ultrasonics Corporation, Danbury, Conn.) in 2 fifteensecond bursts. Unlysed cells and debris are removed by centrifugation at100×g for 10 min. Membranes are then harvested by centrifugation at45,000×g for 30 minutes. Pelleted membranes are resuspended to 3-10 mgprotein per ml, protein concentration being determined according to themethod of Bradford [Bradford, M., Anal. Biochem., 72, 248 (1976)].Resuspended membranes are then stored frozen at −80° C. until use.

[1011] Binding Assay: Frozen membranes prepared as above are thawed anddiluted to 1 mg protein per ml in Buffer A. One volume of membranepreparation is combined with 0.05 volume test compound or buffer and onevolume of 3 nM 3H-prostaglandin E2 (#TRK 431, Amersham, ArlingtonHeights, Ill.) in Buffer A. The mixture (205 μL total volume) isincubated for 1 hour at 25° C. The membranes are then recovered byfiltration through type GF/C glass fiber filters (#1205-401, Wallac,Gaithersburg, Md.) using a Tomtec harvester (Model Mach II/96, Tomtec,Orange, Conn.). The membranes with bound 3H-prostaglandin E2 are trappedby the filter, the buffer and unbound 3H-prostaglandin E2 pass throughthe filter into waste. Each sample is then washed 3 times with 3 ml of[50 mM Tris-HCl (pH 7.4), 10 mM MgCl₂, 1 mM EDTA]. The filters are thendried by heating in a microwave oven. To determine the amount of3H-prostaglandin bound to the membranes, the dried filters are placedinto plastic bags with scintillation fluid and counted in a LKB 1205Betaplate reader (Wallac, Gaithersburg, Md.). IC50s are determined fromthe concentration of test compound required to displace 50% of thespecifically bound 3H-prostaglandin E2.

[1012] Fracture Healing Assays

[1013] Assay for Effects on Fracture Healing After SystemicAdministration

[1014] Fracture Technique: Sprage-Dawley rats at 3 months of age areanesthetized with Ketamine. A 1 cm incision is made on the anteromedialaspect of the proximal part of the right tibia or femur. The followingdescribes the tibial surgical technique. The incision is carried throughto the bone, and a 1 mm hole is drilled 4 mm proximal to the distalaspect of the tibial tuberosity 2 mm medial to the anterior ridge.Intramedullary nailing is performed with a 0.8 mm stainless steel tube(maximum load 36.3 N, maximum stiffness 61.8 N/mm, tested under the sameconditions as the bones). No reaming of the medullary canal isperformed. A standardized closed fracture is produced 2 mm above thetibiofibular junction by three-point bending using specially designedadjustable forceps with blunt jaws. To minimize soft tissue damage, careis taken not to displace the fracture. The skin is closed withmonofilament nylon sutures. The operation is performed under sterileconditions. Radiographs of all fractures are taken immediately afternailing, and animals with fractures outside the specified diaphysealarea or with displaced nails are excluded. The remaining animals aredivided randomly into the following groups with 10-12 animals per eachsubgroup for testing the fracture healing. The first group receivesdaily gavage of vehicle (water: 100% Ethnanol=95:5) at 1 ml/rat, whilethe others receive daily gavage from 0.01 to 100 mg/kg/day of thecompound to be tested (1 ml/rat) for 10, 20, 40 and 80 days.

[1015] At 10, 20, 40 and 80 days, 10-12 rats from each group areanesthetized with Ketamine and autopsied by exsanguination. Bothtibiofibular bones are removed by dissection and all soft tissue isstripped. Bones from 5-6 rats for each group are stored in 70% ethanolfor histological analysis, and bones from another 5-6 rats for eachgroup are stored in a buffered Ringer's solution (+4° C., pH 7.4) forradiographs and biomechanical testing which is performed.

[1016] Histological Analysis: The methods for histologic analysis offractured bone have been previously published by Mosekilde and Bak (TheEffects of Growth Hormone on Fracture Healing in Rats: A HistologicalDescription. Bone, 14:19-27, 1993). Briefly, the fracture side is sawed8 mm to each side of the fracture line, embedded undecalcified inmethymethacrylate, and cut frontals sections on a Reichert-Jung Polycutmicrotome in 8 μm thick. Masson-Trichrome stained mid-frontal sections(including both tibia and fibula) are used for visualization of thecellullar and tissue response to fracture healing with and withouttreatment. Sirius red stained sections are used to demonstrate thecharacterisitics of the callus structure and to differentiate betweenwoven bone and lamellar bone at the fracture site. The followingmeasurements are performed: (1) fracture gap—measured as the shortestdistance between the cortical bone ends in the fracture, (2) calluslength and callus diameter, (3) total bone volume area of callus, (4)bony tissue per tissue area inside the callus area, (5) fibrous tissuein the callus, (6) cartilage area in the callus.

[1017] Biomechanical Analysis: The methods for biomechanical analysishave been previously published by Bak and Andreassen (The Effects ofAging on Fracture Healing in Rats. Calcif Tissue Int 45:292-297, 1989).Briefly, radiographs of all fractures are taken prior to thebiomechanical test. The mechanical properties of the healing fracturesare analyzed by a destructive three- or four-point bending procedure.Maximum load, stiffness, energy at maximum load, deflection at maximumload, and maximum stress are determined.

[1018] Assay for Effects on Fracture Healing after Local Administration

[1019] Fracture Technique: female or male beagle dogs at approximately 2years of age are used in the study. Transverse radial fractures areproduced by slow continuous loading in three-point bending as describedby Lenehan et al. (Lenehan, T. M.; Balligand, M.; Nunamaker, D. M.;Wood, F. E.: Effects of EHDP on Fracture Healing in Dogs. J Orthop Res3:499-507; 1985). The wire is pulled through the fracture site to ensurecomplete anatomical disruption of the bone. Thereafter, local deliveryof prostaglandin agonists to the fracture site is achieved by slowrelease of compound delivered by slow release pellets or Alzet minipumpsfor 10, 15, or 20 weeks.

[1020] Histological Analysis: The methods for histologic analysis offractured bone have been previously published by Peter et al. (Peter, C.P.; Cook, W. O.; Nunamaker, D. M.; Provost, M. T.; Seedor, J. G.; Rodan,G. A. Effects of alendronate on fracture healing and bone remodeling indogs. J. Orthop. Res. 14:74-70, 1996) and Mosekilde and Bak (The Effectsof Growth Hormone on Fracture Healing in Rats: A HistologicalDescription. Bone, 14:19-27, 1993). Briefly, the fracture side is sawed3 cm to each side of the fracture line, embedded undecalcified inmethymethacrylate, and cut on a Reichert-Jung Polycut microtome in 8 μmthick of frontal sections. Masson-Trichrome stained mid-frontal sections(including both tibia and fibula) are used for visualization of thecellullar and tissue response to fracture healing with and withouttreatment. Sirius red stained sections are used to demonstrate thecharacterisitics of the callus structure and to differentiate betweenwoven bone and lamellar bone at the fracture site. The followingmeasurements are performed: (1) fracture gap—measured as the shortestdistance between the cortical bone ends in the fracture, (2) calluslength and callus diameter, (3) total bone volume area of callus, (4)bony tissue per tissue area inside the callus area, (5) fibrous tissuein the callus, (6) cartilage area in the callus.

[1021] Biomechanical Analysis: The methods for biomechanical analysishave been previously published by Bak and Andreassen (The Effects ofAging on Fracture Healing in Rats. Calcif Tissue Int 45:292-297, 1989)and Peter et al. (Peter, C. P.; Cook, W. O.; Nunamaker, D. M.; Provost,M. T.; Seedor, J. G.; Rodan, G. A. Effects of Alendronate On FractureHealing And Bone Remodeling In Dogs. J. Orthop. Res. 14:74-70, 1996).Briefly, radiographs of all fractures are taken prior to thebiomechanical test. The mechanical properties of the healing fracturesare analyzed by a destructive three- or four-point bending procedures.Maximum load, stiffness, energy at maximum load, deflection at maximumload, and maximum stress are determined.

[1022] Estrogen Agonist/Antagonist Protocol

[1023] Estrogen agonist/antagonists are a class of compounds whichinhibits bone turnover and prevents estrogen-deficiency induced boneloss. The ovariectomized rat bone loss model has been widely used as amodel of postmenopausal bone loss. Using this model, one can test theefficacy of the estrogen agonist/antagonist compounds in preventing boneloss and inhibiting bone resorption.

[1024] Sprague-Dawley female rats (Charles River, Wilmington, Mass.) atdifferent ages (such as 5 months of age) are used in these studies. Therats are singly housed in 20 cm×32 cm×20 cm cages during theexperimental period. All rats are allowed free access to water and apelleted commercial diet (Agway ProLab 3000, Agway County Food, Inc.,Syracuse, N.Y.) containing 0.97% calcium, 0.85% phosphorus, and 1.05IU/g of Vit.D₃

[1025] A group of rats (8 to 10) are sham-operated and treated p.o. withvehicle (10% ethanol and 90% saline, 1 ml/day), while the remaining ratsare bilaterally ovariectomized (OVX) and treated with either vehicle(p.o.), 17β-estradiol (Sigma, E-8876, E₂, 30 μg/kg, daily subcutaneousinjection), or estrogen agonist/antagonists (such as droloxifene at 5,10, or 20 mg/kg, daily p.o.) for a certain period (such as 4 weeks). Allrats are given subcutaneous injections of 10 mg/kg calcein (fluorochromebone marker) 12 and 2 days before being sacrificed in order to examinethe dynamic changes in bone tissue. After 4 weeks of treatment, the ratsare sacrificed and autopsied. The following endpoints are determined:

[1026] Body Weight Gain: body weight at autopsy minus body weight atsurgery.

[1027] Uterine Weight and Histology: The uterus is removed from each ratduring autopsy, and weighed immediately. Thereafter, the uterus isprocessed for histologic measurements such as uterine cross-sectionaltissue area, stromal thickness, and luminal epithelial thickness.

[1028] Total Serum Cholesterol: Blood is obtained by cardiac punctureand allowed to clot at 4° C., and then centrifuged at 2,000 g for 10min. Serum samples are analyzed for total serum cholesterol using a highperformance cholesterol calorimetric assay (Boehringer MannheimBiochemicals, Indianapolis, Ind.).

[1029] Femoral Bone Mineral Measurements: The right femur from each ratis removed at autopsy and scanned using dual energy x-ray absorptiometry(DEXA, QDR 1000/W, Hologic Inc., Waltham, Mass.) equipped with “RegionalHigh Resolution Scan” software (Hologic Inc., Waltham, Mass.). The scanfield size is 5.08×1.902 cm, resolution is 0.0254×0.0127 cm and scanspeed is 7.25 mm/second. The femoral scan images are analyzed and bonearea, bone mineral content (BMC), and bone mineral density (BMD) ofwhole femora (WF), distal femoral metaphyses (DFM), femoral shaft (FS),and proximal femora (PF) is determined

[1030] Proximal Tibial Metaphyseal Cancellous Bone HistomorphometricAnalyses: The right tibia is removed at autopsy, dissected free ofmuscle, and cut into three parts. The proximal tibia is fixed in 70%ethanol, dehydrated in graded concentrations of ethanol, defatted inacetone, then embedded in methyl methacrylate (Eastman OrganicChemicals, Rochester, N.Y.). Frontal sections of proximal tibialmetaphyses at 4 and 10 μm thickness are cut using Reichert-Jung PolycutS microtome. One 4 μm and one 10 μm sections from each rat are used forcancellous bone histomorphometry. The 4 μm sections are stained withmodified Masson's Trichrome stain while the 10 μm sections remainedunstained.

[1031] A Bioquant OS/2 histomorphometry system (R&M biometrics, Inc.,Nashville, Tenn.) is used for the static and dynamic histomorphometricmeasurements of the secondary spongiosa of the proximal tibialmetaphyses between 1.2 and 3.6 mm distal to the growth plate-epiphysealjunction. The first 1.2 mm of the tibial metaphyseal region is omittedin order to restrict measurements to the secondary spongiosa. The 4 μmsections are used to determine indices related to bone volume, bonestructure, and bone resorption, while the 10 μm sections are used todetermine indices related to bone formation and bone turnover.

[1032] I. Measurements and calculations related to trabecular bonevolume and structure:

[1033] 1. Total metaphyseal area (TV, mm²): metaphyseal area between 1.2and 3.6 mm distal to the growth plate-epiphyseal junction.

[1034] 2. Trabecular bone area (BV, mm²): total area of trabeculaewithin TV.

[1035] 3. Trabecular bone perimeter (BS, mm): the length of totalperimeter of trabeculae.

[1036] 4. Trabecular bone volume (BV/TV, %): BV/TV×100.

[1037] 5. Trabecular bone number (TBN, #/mm): 1.199/2×BS/TV.

[1038] 6. Trabecular bone thickness (TBT, μm): (2000/1.199)×(BV/BS).

[1039] 7. Trabecular bone separation (TBS, μm): (2000×1.199)×(TV−BV).

[1040] II. Measurements and calculations related to bone resorption:

[1041] 1. Osteoclast number (OCN, #): total number of osteoclast withintotal metaphyseal area.

[1042] 2. Osteoclast perimeter (OCP, mm): length of trabecular perimetercovered by osteoclast.

[1043] 3. Osteoclast number/mm (OCN/mm, #/mm): OCN/BS.

[1044] 4. Percent osteoclast perimeter (% OCP, %): OCP/BS×100.

[1045] III. Measurements and calculations related to bone formation andturnover:

[1046] 1. Single-calcein labeled perimeter (SLS, mm): total length oftrabecular perimeter labeled with one calcein label.

[1047] 2. Double-calcein labeled perimeter (DLS, mm): total length oftrabecular perimeter labeled with two calcein labels.

[1048] 3. Inter-labeled width (ILW, μm): average distance between twocalcein labels.

[1049] 4. Percent mineralizing perimeter (PMS, %): (SLS/2+DLS)/BS×100.

[1050] 5. Mineral apposition rate (MAR, μm/day): ILW/label interval.

[1051] 6. Bone formation rate/surface ref. (BFR/BS, μm²/d/μm):(SLS/2+DLS)×MAR/BS.

[1052] 7. Bone turnover rate (BTR, %/y): (SLS/2+DLS)×MAR/BV×100.

[1053] Statistics

[1054] Statistics are calculated using StatView 4.0 packages (AbacusConcepts, Inc., Berkeley, Calif.). The analysis of variance (ANOVA) testfollowed by Fisher's PLSD is used to compare the differences betweengroups.

[1055] Combination and Sequential Treatment Protocol

[1056] The following protocols can of course be varied by those skilledin the art. For example, intact male or female rats, sex hormonedeficient male (orchidectomy) or female (ovariectomy) rats may be used.In addition, male or female rats at different ages (such as 12 months ofage) can be used in the studies. The rats can be either intact orcastrated (ovariectomized or orchidectomized), and administrated withanabolic agents such as the compounds of this invention at differentdoses (such as 1, 3 or 6 mg/kg/day) for a certain period (such as twoweeks to two months), and followed by administration of ananti-resorptive agent such as droloxifene at different doses (such as1,5,10 mg/kg/day) for a certain period (such as two weeks to twomonths), or a combination treatment with both anabolic agent andanti-resorptive agent at different doses for a certain period (such astwo weeks to two months). In the castrated rats, treatment can bestarted at the next day after surgery (for the purpose of preventingbone loss) or at the time bone loss has already occurred (for thepurpose of restoring bone mass).

[1057] The rats are sacrificed under ketamine anesthesia. The followingendpoints are determined:

[1058] Femoral Bone Mineral Measurements: The right femur from each ratis removed at autopsy and scanned using dual energy x-ray absorptiometry(DXA, QDR 1000/W, Hologic Inc., Waltham, Mass.) equipped with “RegionalHigh Resolution Scan” software (Hologic Inc., Waltham, Mass.). The scanfield size is 5.08×1.902 cm, resolution is 0.0254×0.0127 cm and scanspeed is 7.25 mm/second. The femoral scan images are analyzed and bonearea, bone mineral content (BMC), and bone mineral density (BMD) ofwhole femora (WF), distal femoral metaphyses (DFM), femoral shaft (FS),and proximal femora (PF) are determined.

[1059] Lumbar Vertebral Bone Mineral Measurements: Dual energy x-rayabsorptiometry (QDR 1000/W, Hologic, Inc., Waltham, Mass.) equipped witha “Regional High Resolution Scan” software (Hologic, Inc., Waltham,Mass.) is used to determined the bone area, bone mineral content (BMC),and bone mineral density (BMD) of whole lumbar spine and each of the sixlumbar vertebrae (LV1-6) in the anesthetized rats. The rats areanesthetized by injection (i.p.) of 1 ml/kg of a mixture ofketamine/rompun (ratio of 4 to 3), and then placed on the rat platform.The scan field sized is 6×1.9 cm, resolution is 0.0254×0.0127 cm, andscan speed is 7.25 mm/sec. The whole lumbar spine scan image is obtainedand analyzed. Bone area (BA), and bone mineral content (BMC) isdetermined, and bone mineral density is calculated (MBC divided by BA)for the whole lumbar spine and each of the six lumbar vertebrae (LV1-6).

[1060] Proximal Tibial Metaphyseal Cancellous Bone HistomorphometricAnalyses: The right tibia is removed at autopsy, dissected free ofmuscle, and cut into three parts. The proximal tibia is fixed in 70%ethanol, dehydrated in graded concentrations of ethanol, defatted inacetone, then embedded in methyl methacrylate (Eastman OrganicChemicals, Rochester, N.Y.). Frontal sections of proximal tibialmetaphyses at 4 and 10 μm thickness is cut using Reichert-Jung Polycut Smicrotome. One 4 μm and one 10 μm sections from each rat is used forcancellous bone histomorphometry. The 4 μm sections is stained withmodified Masson's Trichrome stain while the 10 μm sections remainedunstained.

[1061] A Bioquant OS/2 histomorphometry system (R&M biometrics, Inc.,Nashville, Tenn.) is used for the static and dynamic histomorphometricmeasurements of the secondary spongiosa of the proximal tibialmetaphyses between 1.2 and 3.6 mm distal to the growth plate-epiphysealjunction. The first 1.2 mm of the tibial metaphyseal region needs to beomitted in order to restrict measurements to the secondary spongiosa.The 4 μm sections are used to determine indices related to bone volume,bone structure, and bone resorption, while the 10 μm sections are usedto determine indices related to bone formation and bone turnover.

[1062] I. Measurements and calculations related to trabecular bonevolume and structure:

[1063] 1. Total metaphyseal area (TV, mm²): metaphyseal area between 1.2and 3.6 mm distal to the growth plate-epiphyseal junction.

[1064] 2. Trabecular bone area (BV, mm²): total area of trabeculaewithin TV.

[1065] 3. Trabecular bone perimeter (BS, mm): the length of totalperimeter of trabeculae.

[1066] 4. Trabecular bone volume (BV/TV, %): BV/TV×100.

[1067] 5. Trabecular bone number (TBN, #/mm): 1.199/2×BS/TV.

[1068] 6. Trabecular bone thickness (TBT, μm): (2000/1.199)×(BV/BS).

[1069] 7. Trabecular bone separation (TBS, μm): (2000×1.199)×(TV−BV).

[1070] II. Measurements and calculations related to bone resorption:

[1071] 1. Osteoclast number (OCN, #): total number of osteoclast withintotal metaphyseal area.

[1072] 2. Osteoclast perimeter (OCP, mm): length of trabecular perimetercovered by osteoclast.

[1073] 3. Osteoclast number/mm (OCN/mm, #/mm): OCN/BS.

[1074] 4. Percent osteoclast perimeter (%OCP, %): OCP/BS×100.

[1075] III. Measurements and calculations related to bone formation andturnover:

[1076] 1. Single-calcein labeled perimeter (SLS, mm): total length oftrabecular perimeter labeled with one calcein label.

[1077] 2. Double-calcein labeled perimeter (DLS, mm): total length oftrabecular perimeter labeled with two calcein labels.

[1078] 3. Inter-labeled width (ILW, μm): average distance between twocalcein labels.

[1079] 4. Percent mineralizing perimeter (PMS, %): (SLS/2+DLS)/BS×100.

[1080] 5. Mineral apposition rate (MAR, μm/day): ILW/label interval.

[1081] 6. Bone formation rate/surface ref. (BFR/BS, μm²/d/μm):(SLS/2+DLS)×MAR/BS.

[1082] 7. Bone turnover rate (BTR, %/y): (SLS/2+DLS)×MAR/BV×100.

[1083] Statistics

[1084] Statistics can be calculated using StatView 4.0 packages (AbacusConcepts, Inc., Berkeley, Calif.). The analysis of variance (ANOVA) testfollowed by Fisher's PLSD can be used to compare the differences betweengroups.

[1085] Use of a Prostaglandin Receptor Agonist in Kidney Regeneration.

[1086] The role of a prostaglandin agonist in kidney regeneration wasinvestigated by the ability of PGE₂ or a prostaglandin agonist to inducethe expression of Bone Morphogenetic Protein 7 (BMP-7) in wild type 293Scells and in 293S cells transfected with the EP₂ receptor.

[1087] Methods: 293S and EP2 293S cells were grown in Dulbecco'sModified Egale medium (DMEM, Gibco, BRL; Gaithersburg, Md.). One dayprior to treatment with PGE₂ or a prostaglandin agonist, cells wereplated at a density of 1.5×10⁶ cells/10 cm dish. The next day the cellmonolayer was washed once with OptiMEM (Gibco, BRL) followed by theaddition of 10 mL OptiMEM/dish in the presence and absense of vehicle(DMSO), PGE2 (10⁻⁶M) or prostaglandin agonist (10⁻⁶M). Cells wereharvested and RNA extracted at 8, 16 and 24 hours. Northern blotanalysis of total (20 mg/lane ) was carried out by probing the blotswith ³²P-labeled BMP-7 probe. The blots were normalized for RNA loadingby hybridization with ³²P-labeled 18s ribosomal RNA probe. It wasobserved that both PGE₂ and the prostaglandin agonist in a timedependent manner induce the expression of BMP-7 in the EP₂ 293S cellsbut not in the parental cell line. Given the known role of BMP-7 inkidney regeneration and the ability of a prostaglandin agonist to induceBMP-7 expression in 293S kidney cells in a time and receptor specificmanner indicates a role for a prostaglandin agonist in kidneyregeneration.

[1088] Administration of the compounds of this invention can be via anymethod which delivers a compound of this invention systemically and/orlocally (e.g., at the site of the bone fracture, osteotomy, ororthopedic surgery). These methods include oral routes, parenteral,intraduodenal routes, etc. Generally, the compounds of this inventionare administered orally, but parenteral administration (e.g.,intravenous, intramuscular, subcutaneous or intramedullary) may beutilized, for example, where oral administration is inappropriate forthe target or where the patient is unable to ingest the drug.

[1089] The compounds are used for the treatment and promotion of healingof bone fractures and osteotomies by the local application (e.g., to thesites of bone fractures or osteotomies) of the compounds of thisinvention or compositions thereof. The compounds of this invention areapplied to the sites of bone fractures or osteotomies, for example,either by injection of the compound in a suitable solvent (e.g., an oilysolvent such as arachis oil) to the cartilage growth plate or, in casesof open surgery, by local application thereto of such compounds in asuitable carrier such as bone-wax, demineralized bone powder, polymericbone cements, bone sealants etc. Alternatively, local application can beachieved by applying a solution or dispersion of the compound in asuitable carrier onto the surface of, or incorporating it into solid orsemi-solid implants conventionally used in orthopedic surgery, such asdacron-mesh, Gore-tex®, gel-foam and kiel bone, or prostheses.

[1090] The compounds of this invention may also be applied locally tothe site of the fracture or osteotomy in a suitable carrier incombination with one or more of the anabolic agents or boneanti-resorptive agents described above.

[1091] The two different compounds of this invention can beco-administered simultaneously or sequentially in any order, or a singlepharmaceutical composition comprising a Formula I compound as describedabove and a second compound as described above in a pharmaceuticallyacceptable carrier can be administered.

[1092] For example, the bone anabolic agent can be used alone or incombination with an anti-resorptive agent for one week to three years,followed by an anti-resorptive agent alone for three months to threeyears, with optional repeat of the full treatment cycle. Alternatively,for example, the bone anabolic agent can be used alone or in combinationwith an anti-resorptive agent for three months to three years, followedby an anti-resorptive agent alone for the remainder of the patient'slife. For example, in one preferred mode of administration a Formula Icompound as described above may be administered once daily and a secondcompound as described above (e.g., estrogen agonist/antagonist) may beadministered daily in single or multiple doses. Alternatively, forexample, in another preferred mode of administration the two compoundsmay be administered sequentially wherein the Formula I compound asdescribed above may be administered once daily for a period of timesufficient to augment bone mass to a level which is above the bonefracture threshold (World Health Organization Study “Assessment ofFracture Risk and its Application to Screening for PostmenopausalOsteoporosis (1994). Report of a World Health Organization Study Group.World Health Organization Technical Series 843”) followed byadministration of a second compound, as described above (e.g., estrogenagonist/antagonist), daily in single or multiple doses. It is preferredthat the first compound as described above is administered once daily ina rapid delivery form such as oral delivery (e.g., sustained releasedelivery form is preferably avoided).

[1093] In any event the amount and timing of compounds administeredwill, of course, be dependent on the subject being treated, on theseverity of the affliction, on the manner of administration and on thejudgement of the prescribing physician. Thus, because of patient topatient variability, the dosages given below are a guideline and thephysician may titrate doses of the drug to achieve the treatment (e.g.,bone mass augmentation) that the physician considers appropriate for thepatient. In considering the degree of treatment desired, the physicianmust balance a variety of factors such as bone mass starting level, ageof the patient, presence of preexisting disease, as well as presence ofother diseases (e.g., cardiovascular disease).

[1094] In general an amount of a compound of this invention is used thatis sufficient to augment bone mass to a level which is above the bonefracture threshold (as detailed in the World Health Organization Studypreviously cited herein).

[1095] In general an effective dosage for the anabolic agents describedabove is in the range of 0.001 to 100 mg/kg/day, preferably 0.01 to 50mg/kg/day.

[1096] The following paragraphs provide preferred dosage ranges forvarious anti-resorptive agents.

[1097] The amount of the anti-resorptive agent to be used is determinedby its activity as a bone loss inhibiting agent. This activity isdetermined by means of an individual compound's pharmacokinetics and itsminimal maximal effective dose in inhibition of bone loss using aprotocol such as described above (e.g., ESTROGEN AGONIST/ANTAGONISTPROTOCOL).

[1098] In general, an effective dosage for an anti-resorptive agent isabout 0.001 mg/kg/day to about 20 mg/kg/day.

[1099] In general, an effective dosage for progestins is about 0.1 to 10mg per day; the preferred dose is about 0.25 to 5 mg per day.

[1100] In general, an effective dosage for polyphosphonates isdetermined by its potency as a bone resorption inhibiting agentaccording to standard assays.

[1101] Ranges for the daily administration of some polyphosphonates areabout 0.001 mg/kg/day to about 20 mg/kg/day.

[1102] In general an effective dosage for the treatment of thisinvention, for example the bone resorption treatment of this invention,for the estrogen agonists/antagonists of this invention is in the rangeof 0.01 to 200 mg/kg/day, preferably 0.5 to 100 mg/kg/day.

[1103] In particular, an effective dosage for droloxifene is in therange of 0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

[1104] In particular, an effective dosage for raloxifene is in the rangeof 0.1 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.

[1105] In particular, an effective dosage for tamoxifen is in the rangeof 0.1 to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

[1106] In particular, an effective dosage for

[1107]Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[1108](−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[1109]Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

[1110]Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;

[1111]1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

[1112]Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or

[1113]1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline

[1114] is in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to10 mg/kg/day.

[1115] In particular, an effective dosage for 4-hydroxy tamoxifen is inthe range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.

[1116] The compounds of the present invention are generally administeredin the form of a pharmaceutical composition comprising at least one ofthe compounds of this invention together with a pharmaceuticallyacceptable vehicle or diluent. Thus, the compounds of this invention canbe administered individually or together in any conventional oral,parenteral, rectal or transdermal dosage form.

[1117] For oral administration a pharmaceutical composition can take theform of solutions, suspensions, tablets, pills, capsules, powders, andthe like. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the compounds of this invention can be combined withvarious sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

[1118] For purposes of parenteral administration, solutions in sesame orpeanut oil or in aqueous propylene glycol can be employed, as well assterile aqueous solutions of the corresponding water-soluble salts. Suchaqueous solutions may be suitably buffered, if necessary, and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseaqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal injection purposes. Inthis connection, the sterile aqueous media employed are all readilyobtainable by standard techniques well-known to those skilled in theart.

[1119] For purposes of transdermal (e.g.,topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

[1120] Methods of preparing various pharmaceutical compositions with acertain amount of active ingredient are known, or will be apparent inlight of this disclosure, to those skilled in this art. For examples ofmethods of preparing pharmaceutical compositions, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15thEdition (1975).

[1121] Pharmaceutical compositions according to the invention maycontain 0.1%-95% of the compound(s) of this invention, preferably1%-70%. In any event, the composition or formulation to be administeredwill contain a quantity of a compound(s) according to the invention inan amount effective to treat the disease/condition of the subject beingtreated, e.g., a bone disorder.

[1122] Since the present invention has an aspect that relates to theaugmentation and maintenance of bone mass by treatment with acombination of active ingredients which may be administered separately,the invention also relates to combining separate pharmaceuticalcompositions in kit form. The kit comprises two separate pharmaceuticalcompositions: a compound of Formula I and a second compound as describedabove. The kit comprises container means for containing the separatecompositions such as a divided bottle or a divided foil packet.Typically the kit comprises directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

[1123] An example of such a kit is a so-called blister pack. Blisterpacks are well known in the packaging industry and are being widely usedfor the packaging of pharmaceutical unit dosage forms (tablets,capsules, and the like). Blister packs generally consist of a sheet ofrelatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process recesses areformed in the plastic foil. The recesses have the size and shape of thetablets or capsules to be packed. Next, the tablets or capsules areplaced in the recesses and the sheet of relatively stiff material issealed against the plastic foil at the face of the foil which isopposite from the direction in which the recesses were formed. As aresult, the tablets or capsules are sealed in the recesses between theplastic foil and the sheet. Preferably the strength of the sheet is suchthat the tablets or capsules can be removed from the blister pack bymanually applying pressure on the recesses whereby an opening is formedin the sheet at the place of the recess. The tablet or capsule can thenbe removed via said opening.

[1124] It may be desirable to provide a memory aid on the kit, e.g., inthe form of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also a daily dose of Formula I compound canconsist of one tablet or capsule while a daily dose of the secondcompound can consist of several tablets or capsules and vice versa. Thememory aid should reflect this.

[1125] In another specific embodiment of the invention a dispenserdesigned to dispense the daily doses one at a time in the order of theirintended use is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

[1126] The compounds of this invention either alone or in combinationwith each other or other compounds generally will be administered in aconvenient formulation. The following formulation examples only areillustrative and are not intended to limit the scope of the presentinvention.

[1127] In the formulations which follow, “active ingredient” means acompound of this invention. Formulation 1: Gelatin Capsules Hard gelatincapsules are prepared using the following: Ingredient Quantity(mg/capsule) Active ingredient 0.25-100  Starch, NF  0-650 Starchflowable powder  0-50 Silicone fluid 350 centistokes  0-15 A tabletformulation is prepared using the ingredients below: Formulation 2:Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.25-100 Cellulose, microcrystalline 200-650 Silicon dioxide, fumed  10-650Stearate acid  5-15

[1128] The components are blended and compressed to form tablets.

[1129] Alternatively, tablets each containing 0.25-100 mg of activeingredients are made up as follows: Formulation 3: Tablets IngredientQuantity (mg/tablet) Active ingredient 0.25-100 Starch 45 Cellulose,microcrystalline 35 Polyvinylpyrrolidone (as 10% solution in water) 4Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1

[1130] The active ingredients, starch, and cellulose are passed througha No. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

[1131] Suspensions each containing 0.25-100 mg of active ingredient per5 ml dose are made as follows: Formulation 4: Suspensions IngredientQuantity (mg/5 ml) Active ingredient 0.25-100 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q.v.Color q.v. Purified Water to 5 mL

[1132] The active ingredient are passed through a No. 45 mesh U.S. sieveand mixed with the sodium carboxymethyl cellulose and syrup to formsmooth paste. The benzoic acid solution, flavor, and color are dilutedwith some of the water and added, with stirring. Sufficient water isthen added to produce the required volume. An aerosol solution isprepared containing the following ingredients: Formulation 5: AerosolIngredient Quantity (% by weight) Active ingredient  0.25 Ethanol 25.75Propellant 22 (Chlorodifluoromethane) 70.00

[1133] The active ingredient is mixed with ethanol and the mixture addedto a portion of the propellant 22, cooled to 30° C., and transferred toa filling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container. Suppositories are prepared as follows:Formulation 6: Suppositories Ingredient Quantity (mg/suppository) Activeingredient   250 Saturated fatty acid glycerides 2,000

[1134] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

[1135] An intravenous formulation is prepared as follows: Formulation 7:Intravenous Solution Ingredient Quantity Active ingredient 20 mgIsotonic saline 1,000 mL

[1136] The solution of the above ingredients is intravenouslyadministered to a patient at a rate of about 1 mL per minute.

[1137] The active ingredient above may also be a combination of agents.

GENERAL EXPERIMENTAL PROCEDURES

[1138] NMR spectra were recorded on a Varian XL-300 (Varian Co., PaloAlto, Calif.) a Bruker AM-300 spectrometer at about 23° C. at 300 MHzfor proton and 75.4 mHz for carbon (Bruker Co., Billerica, Mass.) or aVarian Unity 400 at 400 Mhz for proton nuclei. Chemical shifts areexpressed in parts per million downfield from trimethylsilane. The peakshapes are denoted as follows: s, singlet; d, doublet; t, triplet, q,quartet; m, multiplet; bs=broad singlet. Resonances designated asexchangeable did not appear in a separate NMR experiment where thesample was shaken with several drops of D₂O in the same solvent.Atmospheric pressure chemical ionization (APCI) mass spectra wereobtained on a Fisons Platform II Spectrometer. Chemical ionization massspectra were obtained on a Hewlett-Packard 5989 instrument(Hewlett-Packard Co., Palo Alto, Calif.) (ammonia ionization, PBMS).Where the intensity of chlorine or bromine-containing ions are describedthe expected intensity ratio was observed (approximately 3:1 for³⁵Cl/³⁷Cl-containing ions) and 1:1 for ⁷⁹Br/⁸¹Br-containing ions) andthe intensity of only the lower mass ion is given.

[1139] Column chromatography was performed with either Baker Silica Gel(40 μm) (J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences,Gibbstown, N.J.) in glass columns under low nitrogen pressure. RadialChromatography was performed using a Chromatron (model 7924T, HarrisonResearch) Unless otherwise specified, reagents were used as obtainedfrom commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran,and dichloromethane used as reaction solvents were the anhydrous gradesupplied by Aldrich Chemical Company (Milwaukee, Wis.). Microanalyseswere performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y.The terms “concentrated” and “coevaporated” refer to removal of solventat water aspirator pressure on a rotary evaporator with a bathtemperature of less than 45° C. Reactions conducted at “0-20° C.” or“0-25° C.” were conducted with initial cooling of the vessel in aninsulated ice bath which was allowed to warm to room temperature overseveral hours. The abbreviation “min” and “h” stand for “minutes” and“hours” respectively.

Example 1 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

[1140] Step A: Alkylation

[1141] Ethyl 7-[(4-Butyl-benzyl)-methanesulfonyl-aminol-heptanoate. Asolution of ethyl-7-methanesulfonyl-amino-heptanoate (250 mg, 1.0 mmol)in DMF (2 mL) was added dropwise to NaH (48 mg, 1.19 mmol, 60% in oil)in DMF at 0° C. After stirring for 45 minutes at room temperature,1-bromomethyl-4-butyl-benzene (271 mg, 1.19 mmol) was added dropwise.The reaction was stirred for 2 h and the DMF was removed in vacuo. Theresidue was diluted with CH₂Cl₂ and the organic solution wassequentially washed with 1N HCl (1×), water (2×), and brine (1×). Theorganic solution was dried over MgSO₄, filtered, and concentrated invacuo. The product was purified via radial chromatography (15%EtOAc/hexanes to 40% EtOAc/hexanes) to afford the title compound of StepA (379 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.30 (m, 4H), 4.35 (s, 2H),4.12 (q, 2H), 3.10-3.19 (m, 2H), 2.80 (s, 3H), 2.60 (t, 2H), 2.25 (t,2H), 1.46-1.62 (m, 7H), 1.18-1.39 (m, 6H), 0.92 (t, 3H); MS 415 (M+18).

[1142] Step B: Ester Hydrolysis

[1143] 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid. To asolution of the title compound of Step A (379 mg, 0.95 mmol) in MeOH (6mL) was added NaOH (1.0 mL, 5N). The reaction was stirred at roomtemperature for 24 h and was acidified with aqueous HCl (1N). The MeOHwas removed in vacuo and the residue was dissolved in CH₂Cl₂. Theorganic solution was washed sequentially with HCl (1N, 1×), water (2×),and brine (1×). The organic solution was dried with MgSO₄, filtered, andconcentrated in vacuo. Purification by radial chromatography (CH₂Cl₂ to6% MeOH/CH₂Cl₂) provided the title compound (356 mg). ¹H NMR (400 MHz,CDCl₃) δ 7.30-7.12 (m, 4H), 4.35 (s, 2H), 3.10-3.19 (m, 2H), 2.80 (s,3H), 2.60 (t, 2H), 2.31 (t, 2H), 1.48-1.65 (m, 7H), 1.20-1.40 (m, 6H).0.97 (t, 3H); MS 387 (M+18).

Examples 2-44

[1144] Examples 2-44 were prepared from the appropriate startingmaterials using the Methods described in SCHEMES 1 and 2 and in ananalogous manner to Example 1 with variations in reaction temperatureand time in Step A as noted.

Example 2(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid

[1145]¹H NMR (400 MHz, CDCl₃) δ 7.32-7.14 (m, 5H), 4.32 (s, 2H), 4.29(s, 2H), 3.66 (s, 2H), 2.76 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.34(m, 2H), 0.93 (t, 3H); MS 388 (M+)

Example 37-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

[1146] Step A: Reaction time of 24 h at room temperature. ¹HNMR (400MHz, CDCl₃) δ 7.00 (m, 1H), 6.80 (m, 2H), 4.12 (t, 2H), 3.60 (t, 2H),3.26 (t, 2H), 4.29 (s, 2H), 3H), 2.37 (t, 2H), 1.65 (m, 4H), 1.39 (m,4H); MS 412 (M+).

Example 44-(2-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-ethyl)-benzoicacid

[1147]¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, 2H), 7.30 (d, 2H), 7.20 (s,1H), 7.19 (s, 2H), 6.39 (d, 1H), 6.08 (m, 1H), 3.94 (m, 2H), 3.50 (t,2H), 3.00 (t, 2H), 2.78 (s, 3H).

Example 5 7-[Methanesulfonyl-(4-trifluoromethyl-benzyl)-amino]-heptanoicacid

[1148]¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, 2H), 7.48 (d, 2H), 4.41 (s,2H), 3.16 (t, 2H), 2.87 (s, 3H), 2.29 (t, 2H), 1.40-1.61 (m, 4H),1.13-1.33 (m, 4H).

Example 6 Trans-7-[Methanesulfonyl-(3-phenyl-allyl)-amino]-heptanoicacid

[1149] Step A: Reaction time of 24 h at 90° C. ¹H NMR (400 MHz, CDCl₃) δ7.2-7.4 (m, 5H), 6.59 (d, 1H), 6.12-6.21 (m, 1H), 4.0 (d, 2H), 3.21 (t,2H), 2.32 (t, 2H), 1.55-1.70 (m, 4H), 1.27-1.40 (m, 4H); MS 338.1 (M−1).

Example 7Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-aceticacid

[1150] Step A: Reaction time of 2 h at 100° C. ¹H NMR (400 MHz, CDCl₃)δ7.37 (m, 2H), 7.23 (m, 1H), 6.42-6.52 (m, 1H), 6.15-6.28 (m, 1H), 3.96(m, 4H), 3.52 (m, 2H), 3.23 (m, 2H), 2.86 (s, 3H), 1.55-1.72 (m, 4H); MS411.5 (M+1).

Example 87-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoic acid

[1151] Step A: Reaction time of 24 h at 90° C. Mp 68-70° C.; ¹H NMR (400MHz, CDCl₃) δ 7.20-7.38 (m, 4H), 4.62-4.66 (m, 1H), 4.34 (s, 2H),3.10-3.18 (m, 2H), 2.94 (s, 1H), 2.83 (s, 3H), 2.17-2.39 (m, 3H),1.10-1.83 (m, 16H), 0.80-0.90 (m, 3H).

Example 97-[Methanesulfonyl-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-amino]-heptanoicacid

[1152] Step A: Reaction time of 24 h at room temperature. ¹H NMR (CDCl₃400 MHz) δ 7.75-7.23 (m, 8H), 4.46 (s, 2H), 3.21 (t, 2H), 2.84 (s, 3H),2.34 (t, 2H), 1.57 (m, 4H), 1.28 (m, 4H).

Example 107-[(2′,6′-Dichloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid

[1153] Step A: Reaction time of 24 h at room temperature. ¹H NMR (CDCl₃400 MHz) δ 7.60-7.20 (m, 7H), 4.41 (s, 2H), 3.21 (t, 2H), 2.82 (s, 3H),2.30 (t, 2H), 1.56 (m, 4H), 1.27 (m, 4H); MS 458 (M+).

Example 11 7-[Methanesulfonyl-(2-phenoxy-ethyl)-amino]-heptanoic acid

[1154]¹H NMR (400 MHz, CDCl₃) δ 7.25-7.36 (m, 2H), 6.85-7.03 (m, 3H),4.11 (t, 2H), 3.62 (t, 2H), 3.27 (t, 2H), 2.91 (s, 3H), 2.34 (t, 2H),1.72-1.54 (m, 4H), 1.45-1.25 (m, 4H).

Example 127-[(Methylsulfonyl)[[4-(2-pyridinyl)phenyl]methyl]amino]-heptanoic acidhydrochloride salt

[1155] Step A: Reaction time of 45 minutes at room temperature. ¹H NMR(400 MHz, CDCl₃) δ 8.72 (bs, 1H), 7.64-7.95 (m, 4H), 7.48 (d, 2H),7.21-7.32 (m, 1H), 4.40 (s, 2H), 3.14 (t, 2H), 2.85 (s, 3H), 2.15-2.35(m, 2H), 1.40-1.60 (m, 4H), 1.08-1.30 (m, 4H).

Example 13 7-[Methanesulfonyl-(5-phenyl-pentyl)-amino]-heptanoic acid

[1156] Step A: Reaction time of 2 h at room temperature and 18 h at 70°C. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.14 (m, 5H), 3.12 (m, 4H), 2.78 (s,3H), 2.60 (t, 2H), 2.34 (t, 2H), 1.62 (m, 8H), 1.32 (m, 6H).

Example 147-{[2-(2,4-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

[1157] Step A: Reaction time of 20 h at 65° C. ¹H NMR (400 MHz, CDCl₃) δ7.33 (d, 1H), 7.16 (dd, 1H), 6.83 (d, 1H), 4.13 (t, 2H), 3.62 (t, 2H),3.31 (t, 2H), 2.94 (s, 3H), 2.31 (m, 2H), 1.61 (m, 4H), 1.33 (m, 4H).

Example 15Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1158]¹H NMR (400 MHz, CDCl₃) δ 7.32-7.13 (m, 7H), 6.33 (d, 1H), 6.09(m, 1H), 4.38 (s, 2H), 3.91 (d, 2H), 3.61 (s, 2H), 2.89 (s, 3H).

Example 167-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid

[1159] Step A: Reaction time of 60° C. for 72 h. ¹H NMR (400 MHz, CDCl₃)δ 7.25 (s, 1H), 7.19 (s, 2H), 3.15 (m, 4H), 2.81 (s, 3H), 2.60 (t, 2H),2.34 (t, 2H), 1.89 (m, 2H), 1.60 (m, 4H), 1.32 (m, 4H).

Example 17[3-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1160] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.31-6.91 (m, 8H), 4.34 (s, 2H), 3.64 (s, 2H), 3.18 (t,2H), 2.81 (s, 3H), 2.49 (t, 2H), 1.78 (m, 2H); MS 413 (M+18).

Example 18 7-[(2-Indan-2-yl-ethyl)-methanesulfonyl-amino]-heptanoic acid

[1161] Step A: Reaction time of 4 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.13 (m, 4H), 3.24 (t, 2H), 3.17 (t, 2H), 3.08 (m, 2H),2.83 (s, 3H), 2.62 (m, 2H), 2.48 (m, 1H), 2.35 (t, 2H), 1.81 (m, 2H),1.62 (m, 4H), 1.37 (m, 4H).

Example 19 7-[Methanesulfonyl-(4-phenyl-butyl)-amino]-heptanoic acid

[1162] Step A: Reaction time of 72 h at 60° C. ¹H NMR (400 MHz, CDCl₃) δ7.26 (m, 2H), 7.17 (m, 3H), 3.16 (t, 2H), 3.10 (t, 2H), 2.78 (s, 3H),2.63 (t, 2H), 2.34 (t, 2H), 1.70-1.51 (m, 8H), 1.32 (m, 4H).

Example 20[3-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1163] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.27 (m, 5H), 4.48 (s, 2H), 3.97 (t, 2H), 3.64 (s, 2H),3.57 (t, 2H), 2.92 (s, 3H).

Example 214-(4-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-phenyl)-butyricacid

[1164] Step A: Reaction time of 1 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.32-6.97 (m, 8H), 3.67 (t, 2H), 2.85 (s, 3H), 2.68 (t,2H), 2.63 (t, 2H), 2.40 (t, 2H), 1.97 (m, 2H), 1.77 (m, 2H).

Example 22[2-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenoxy]-aceticacid

[1165] Step A: Reaction time of 1 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.29-6.71 (m, 8H), 4.64 (s, 2H), 3.44 (t, 2H), 3.23 (m,2H), 2.95 (t, 2H), 2.71 (s, 3H), 2.58 (t, 2H), 1.89 (m, 2H).

Example 23[3-({Methanesulfonyl-[3-(3-trifluoromethyl-phenyl)-propyl]-amino}-methyl)-phenyl]-aceticacid

[1166] Step A: Reaction time of 24 h at room temperature. ¹H NMR (CDCl₃400 MHz) δ 7.42-7.21 (m, 4H), 4.34 (s, 2H), 3.62 (s, 2H), 3.22 (t, 2H),2.81 (s, 3H), 2.56 (t, 2H), 1.79 (m, 2H); MS 447 (M+18).

Example 24 {4-[(4-Butyl-benzyl)-methanesulfonyl-amino]-butoxy}-aceticacid

[1167] Step A: Reaction time of 2 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ7.23 (m, 2H), 7.14 (m, 2H), 4.34 (s, 2H), 4.03 (s, 2H), 3.48 (t, 2H),3.19 (t, 2H), 2.79 (s, 3H), 2.59 (t, 2H), 1.57 (m, 6H), 1.32 (m, 2H),0.91 (t, 3H); MS 370 (M−1).

Example 255-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1168] Step A: Reaction time of 5 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ7.71 (m, 1H), 7.24-7.15 (m, 3H), 7.03 (m, 1H), 6.83 (m, 1H), 3.19 (m,4H), 2.89 (t, 2H), 2.81 (s, 3H), 2.61 (t, 2H), 1.94 (m, 4H).

Example 267-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoicacid

[1169]¹HNMR (400 MHz, CDCl₃) δ 6.87 (d, 1H), 6.81 (d, 1H), 4.86 (t, 1H),4.53 (s, 2H), 3.20 (t, 2H), 2.76 (s, 3H), 2.33 (t, 2H), 1.79 (m, 2H),1.22-1.68 (m, 14H), 0.82-0.92 (m, 3H).

Example 275-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1170] Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.65 (s, 1H), 7.20 (m, 4H), 6.68 (s, 1H), 4.33 (s, 2H), 3.22 (m, 2H),2.81 (m, 5H), 2.59 (m, 2H), 1.84 (m, 2H), 1.57 (m, 2H), 1.33 (m, 2H),0.91 (m, 3H); MS 408 (M−1).

Example 28Trans-7-{[3-(3,5-Difluoro-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

[1171]¹HNMR (400 MHz, CDCl₃) δ 6.87 (m, 2H), 6.70 (m, 1H), 6.50 (d, 1H),6.14-6.25 (m, 1H), 3.98 (d, 2H), 3.20 (t, 2H), 2.85 (s, 3H), 2.32 (t,2H), 1.61 (m, 4H), 1.35 (m, 4H).

Example 297-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid

[1172] Step A: Reaction time of 24 h at room temperature. ¹HNMR (400MHz, CDCl₃) δ 7.04-7.30 (m, 4H), 3.15 (m, 4H), 2.80 (s, 3H), 2.62 (t,2H), 2.35 (t, 2H), 1.90 (m, 2H), 1.50-1.67 (m, 4H), 1.25-1.40 (m, 4H).

Example 30Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1173] Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CD₃OD) δ7.15-7.46 (m, 4H), 6.79 (s, 1H), 6.55 (d, 1H), 6.35 (m, 1H), 3.99 (d,2H), 3.29 (m, 2H), 2.91 (m, 5H), 1.99 (m, 2H); MS 447.7 (M−1).

Example 31 7-[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

[1174] Step A: Reaction time of 72 h at room temperature. ¹HNMR (400MHz, CDCl₃) δ 7.24 (d, 2H), 7.12 (d, 2H), 4.32 (s, 2H), 3.12 (t, 2H),2.79 (s, 3H), 2.45 (d, 2H), 2.30 (t, 2H), 1.85 (m, 1H), 1.45-1.62 (m,4H), 1.16-1.32 (m, 4H), 0.90 (d, 6H).

Example 327-{[3-(2-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid

[1175] Step A: Reaction time of 24 h at room temperature. ¹HNMR (400MHz, CDCl₃) δ 7.10-7.39 (m, 4H), 3.22 (t, 2H), 3.10 (t, 2H), 2.82 (s,3H), 2.73 (t, 2H), 2.35 (t, 2H), 1.86-2.00 (m, 2H), 1.52-1.70 (m, 4H),1.28-1.45 (m, 4H); MS 376 (M+1).

Example 337-[(2′-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

[1176] Step A: Reaction time of 24 h at room temperature. ¹HNMR (400MHz, CDCl₃) δ 7.21-7.50 (m, 8H), 4.44 (s, 2H), 3.15-3.26 (m, 2H), 2.86(s, 3H), 2.27-2.38 (m, 2H), 1.48-1.68 (m, 5H), 1.20-1.38 (m, 4H).

Example 34 7-[(4-Benzyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

[1177]¹HNMR (400 MHz, CDCl₃) δ 7.13-7.30 (m, 9H), 4.32 (s, 2H), 3.98 (s,2H), 3.12 (t, 2H), 2.90 (s, 3H), 2.30 (t, 2H), 2.45-2.60 (m, 4H),1.16-1.32 (m, 4H).

Example 35Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid

[1178] Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.30-7.22 (m, 3H), 7.14 (m, 1H), 6.98-6.82 (m, 3H), 6.34 (d, 1H), 6.09(m, 1H), 4.66 (s, 2H), 4.38 (s, 2H), 3.93 (d, 2H), 2.89 (s, 3H); MS443.8 (M−1).

Example 36(4-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid

[1179] Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.29-7.13 (m, 5H), 6.98-6.82 (m, 3H), 4.65 (s, 2H), 4.29 (s, 4H), 2.76(s, 3H), 2.58 (t, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.91 (t, 3H); MS 405(M+).

Example 373-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethoxy)-benzoicacid

[1180] Step A: Reaction time of 4 h at 100° C. ¹HNMR (400 MHz, CD₃OD) δ7.60 (d, 1H), 7.51 (s, 1H), 7.34 (t, 1H), 7.11 (m, 1H), 6.95 (m, 1H),6.83 (s, 1H), 4.20 (m, 4H), 3.73 (m, 4H), 3.01 (s, 3H); MS 447.8 (M−1).

Example 387-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid

[1181] Step A: Reaction time of 24 h at 65° C. ¹HNMR (400 MHz, CDCl₃) δ7.19 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), 6.76 (m, 1H), 4.09 (t, 2 H),3.59 (t, 2H), 3.25 (t, 2H), 2.89 (s, 3H), 2.33 (t, 2H), 1.63 (m, 4H),1.35 (m, 4H); MS 395 (M+18).

Example 397-[(2′-Cyano-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

[1182] Step A: Reaction time of 6 h at 90° C. ¹HNMR (400 MHz, CDCl₃) δ7.75 (d, 1H), 7.65 (t, 1H), 7.40-7.60 (m, 6H), 4.20 (s, 2H), 3.20 (t,2H), 2.85 (s, 3H), 2.25 (t, 2H), 1.55 (m, 4H), 1.25 (m, 4H); MS 414(M+1).

Example 405-(3-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1183] Step A: Reaction time of 72 h at room temperature. ¹HNMR (400MHz, CDCl₃) δ 7.69 (d, 1H), 6.84 (d, 1H), 6.62 (s, 1H), 6.46 (s, 2H),4.08 (t, 2H), 3.62 (t, 2H), 3.35 (t, 2H), 2.92 (m, 5H), 2.27 (s, 6H),2.07 (m, 2H); MS 411 (M+).

Example 415-(3-{[2-(3,5-Dimethoxy-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1184] Step A: Reaction time of 24 h at room temperature. ¹HNMR (400MHz, CDCl₃) δ 7.69 (d, 1H), 6.84 (d, 1H), 6.09 (m, 1H), 6.01 (m, 2H),4.08 (t, 2H), 3.74 (s, 6H), 3.61 (t, 2H), 3.34 (t, 2H), 2.93 (t, 2H),2.90 (s, 3H), 2.07 (m, 2H); MS 444 (M+1).

Example 425-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1185] Step A: Reaction time of 5 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.70 (d, 1H), 6.97 (m, 1H), 6.84 (d, 1H), 7.22 (d, 2H), 4.08 (t, 2H),3.59 (t, 2H), 3.33 (t, 2H), 2.92 (t, 2H), 2.89 (s, 3H), 2.06 (m, 2H); MS452 (M+1).

Example 43[3-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid

[1186] Step A: Reaction time of 5 h at 100° C. ¹HNMR (400 MHz, CDCl₃) δ7.30-6.85 (m, 8H), 4.66 (s, 2H), 4.32 (s, 2H), 3.18 (t, 2H), 2.82 (s,3H), 2.49 (t, 2H), 1.76 (m, 2H); MS 412 (M+).

Example 44[3-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid

[1187] Step A: Reaction time of 5 h at 100° C. ¹HNMR (400 MHz, CD₃OD) δ7.24 (t, 1H), 6.98 (m, 3H), 6.84 (m, 1H), 6.78 (d, 2H), 4.60 (s, 2H),4.44 (s, 2H), 3.99 (t, 2H), 3.57 (t, 2H), 2.98 (s, 3H); MS 448 (M+).

Example 45Trans-7-{[3-(3-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

[1188] Step A: Heck Coupling

[1189]Trans-Ethyl-7-{[3-(3-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoate

[1190] To a solution of 7-(allyl-methanesulfonyl-amino)-heptanoic acidethyl ester (250 mg, 0.86 mmol), 1-acetyloxy-3-iodo-benzene (225 mg,0.86 mmol), and triethylamine (139 mL, 1 mmol) in DMF (3 mL) was addedpalladium acetate (25 mg). The reaction was heated to 80° C. undernitrogen for 24 h. The mixture was cooled to room temperature andaqueous sodium thiosulfate and CH₂Cl₂ were added. The aqueous solutionwas extracted with CH₂Cl₂ (2×) and the combined organic layers werewashed with water (1×) and brine (1×). The organic solution was driedwith MgSO₄, filtered, and concentrated in vacuo. The product waspurified by radial chromatography (hexanes to 25% EtOAc/hexanes) toafford the title compound of Step A (95 mg). ¹H NMR (CDCl₃ 400 MHz) δ6.88-7.34 (m, 4H), 6.53-6.60 (m, 1H), 6.13-6.20 (m, 1H), 4.10 (q, 2H),3.95 (d, 2H), 3.17-3.21 (m, 2H), 2.85 (s, 3H), 2.24-2.31 (m, 2H), 2.31(s, 3H), 1.56-1.62 (m, 4H), 1.27-1.33 (m, 4H), 1.23 (t, 3H).

[1191] Step B: Ester Hydrolysis

[1192]Trans-7-{[3-(3-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid.

[1193] In an analogous manner to the procedure described in Step B ofExample 1, the title compound of Step A was hydrolyzed to provide thetitle compound (53 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.25 (m, 1H),6.81-6.89 (m, 2H), 6.74-6.77 (m, 1H), 6.50 (d, 1H), 6.08-6.15 (m, 1H),3.95 (d, 2H), 3.16-3.20 (m, 2H), 2.85 (s, 3H), 2.26-2.33 (m, 2H),1.50-1.65 (m, 4H), 1.20-1.38 (m, 4H); MS 353.9 (M−1).

Examples 46-50

[1194] Examples 46-50 were prepared from the appropriate startingmaterials in an analogous manner to Example 45.

Example 46Trans-7-{[3-(2-Hydroxy-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

[1195]¹H NMR (400 MHz, CDCl₃) δ 6.49 (d, 1H), 6.12 (m, 1H), 3.94 (d,2H), 3.18 (t, 2H), 2.85 (s, 3H) 2.31 (t, 2H), 1.58 (m, 4H), 1.32 (m,4H); MS 353.9 (M−1).

Example 47Trans-7-{[3-(3-Hydroxymethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

[1196]¹H NMR (400 MHz, CDCl₃) δ 7.19-7.41 (m, 4H), 6.58 (d, 1H),6.13-6.25 (m, 1H), 4.70 (s, 2H), 3.92-4.02 (m, 2H), 3.15-3.25 (m, 2H),2.85 (s, 3H), 2.29 (t, 2H), 1.52-1.68 (m, 4H), 1.18-1.39 (m, 4H); MS 368(M−1).

Example 48Trans-7-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

[1197]¹H NMR (400 MHz, CDCl₃) δ 7.25 (m, 3H), 4.80 (d, 1H). 6.15-6.28(m, 1H), 3.98 (m, 2H), 3.22 (t, 2H), 2.87 (s, 3H), 2.35 (m, 2H),1.48-1.72 (m, 4H), 1.19-1.42 (m, 4H).

Example 49Trans-7-{[3-(3,5-Bis-trifluoromethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid

[1198]¹H NMR (400 MHz, CDCl₃) δ 7.77 (m, 3H), 6.66 (m, 1H), 6.36 (m,1H), 4.02 (d, 2H), 3.24 (t, 2H), 2.89 (s, 3H), 2.33 (t, 2H), 1.62 (m,4H), 1.35 (m, 4H).

Example 50Trans-7-[Methanesulfonyl-(4-phenyl-but-3-enyl)-amino]-heptanoic acid

[1199]¹H NMR (400 MHz, CDCl₃) δ 7.23 (m, 5H), 6.46 (d, 1H), 6.13 (m,1H), 3.31 (t, 2H), 3.19 (t, 2H), 2.83 (s, 3H), 2.52 (m, 2H), 2.34 (m,2H), 1.62 (m, 4H), 1.35 (m, 4H); MS 353 (M+).

Example 517-{[3-(3,5-Bis-trifluoromethyl-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid

[1200] Hydrogenation

[1201] A solution oftrans-7-{[3-(3,5-bis-trifluoromethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoicacid (210 mg, 0.44 mmol) in MeOH (10 ml) was added to 10% Pd/carbon (200mg). The mixture was placed on a Parr hydrogenator at 50 psi and washydrogenated for 20 h. The reaction was filtered through Celite with theaid of MeOH and the solvent was removed in vacuo. Purification by radialchromatography (2 mm rotary plate, 20:80:0.1 v/v/v EtOAc/hexanes/AcOH)provided the title compound (190 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.69 (s,1H), 7.63 (s, 2H), 3.20 (t, 2H), 3.14 (t, 2H), 2.81 (m, 5H), 2.28 (m,2H), 1.94 (m, 2H), 1.32 (m, 4H); MS 495 (M+18).

Examples 52-54

[1202] Examples 52-54 were prepared from the appropriate startingmaterials in an analogous manner to Example 51.

Example 52 7-[Methanesulfonyl-(3-phenyl-propyl)-amino]-heptanoic acid

[1203]¹H NMR (400 MHz, CDCl₃) δ 7.10-7.30 (m, 5H), 3.18 (t, 2H), 3.13(t, 2H), 2.80 (s, 3H), 2.63 (t, 2H), 2.34 (t, 2H), 1.92 (m, 2H),1.48-2.72 (m, 4H), 1.09-1.42 (m, 4H).

Example 53 7-[Methanesulfonyl-(3-m-tolyl-propyl)-amino]-heptanoic acid

[1204]¹H NMR (400 MHz, CDCl₃) δ 6.94-7.21 (m, 4H), 3.18 (t, 2H), 3.13(t, 2H), 2.80 (s, 3H), 2.59 (t, 2H), 2.34 (t, 2H), 2.32 (s, 3H),2.85-2.97 (m, 2H), 2.50-2.68 (m, 5H), 1.23-1.40 (m, 5H).

Example 547-{[3-(3,5-Difluoro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid

[1205]¹HNMR (400 MHz, CDCl₃) δ 6.60-6.78 (m, 3H), 3.12 (m, 4H), 2.82 (s,3H), 2.64 (t, 2H), 2.37 (t, 2H), 1.92 (m, 2H), 1.50-1.70 (m, 4H),1.18-1.42 (m, 4H).

Example 557-{[4-(1-Hydroxy-3-phenyl-propyl)-benzyl]-methanesulfonyl-amino}-heptanoicacid

[1206] Step A: Grignard Reaction

[1207]Ethyl-7-{[4-(1-Hydroxy-3-phenyl-propyl)-benzyl]-methanesulfonyl-amino}-heptanoate.A solution of ethyl7-[(4-formyl-benzyl]-methanesulfonyl-amino]-heptanoate (200 mg, 0.54mmol) in CH₂Cl₂ (2.5 mL) was cooled to 0° C. Phenethylmagnesium chloride(0.6 mL, 1M in THF, 0.6 mmol) was added dropwise and the reactionmixture was stirred at room temperature for 24 h. Water and HCl (1N)were added and the aqueous solution was extracted with CH₂Cl₂. Theorganic solution was washed with water (1×) followed by brine (1×),dried over MgSO₄, filtered, and concentrated in vacuo. The product waspurified by flash chromatography (10% EtOAc/hex to 40% EtOAc/hex) toafford the title compound of Step A (40 mg). ¹H NMR (400 MHz, CDCl₃) δ7.95 (d, 1H), 7.45 (d, 1H), 7.13-7.40 (m, 7H), 4.65-4.73 (m, 1H),4.32-4.46 (m, 2H), 4.11 (q, 2H), 3.25-3.35 (m, 1H), 3.00-3.22 (m, 2H),2.83 (s, 3H), 2.60-2.81 (m, 1H), 1.96-2.34 (m, 4H), 1.15-1.70 (m, 12H);MS 493 (M+18).

[1208] Step B: Ester Hydrolysis

[1209]7-{[4-(1-Hydroxy-3-phenyl-propyl)-benzyl]-methanesulfonyl-amino}-heptanoicacid. In an analogous manner to the procedure described in Step B ofExample 1, the title compound of Step A was hydrolyzed to afford thetitle compound (11 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, 1H), 7.48 (d,1H), 7.15-7.38 (m, 7H), 4.31-4.50 (m, 2H), 3.02-3.35 (m, 4H), 2.83 (s,3H), 2.60-2.80 (m, 1H), 1.96-2.33 (m, 4H), 1.12-1.61 (m, 8H).

Examples 56-58

[1210] Examples 56-58 were prepared from the appropriate startingmaterials in an analogous manner to Example 55.

Example 567-{[4-(1-Hydroxy-pentyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid

[1211]¹H NMR (400 MHz, CDCl₃) δ 7.35-7.25 (m, 4H), 4.66 (t, 1H), 4.34(s, 2H), 3.15 (t, 2H), 2.82 (s, 3H), 2.25 (t, 2H), 1.85-1.61 (m, 2H),1.55-1.12 (m, 13H), 0.90-0.82 (m, 3H); MS 417 (399+18).

Example 577-{[4-(1-Hydroxy-2-phenyl-ethyl)-benzyl]-methanesulfonyl-amino}-heptanoicacid

[1212]¹H NMR (400 MHz, CDCl₃) δ 7.15-7.35 (m, 9H), 4.85-4.97 (m, 1H),4.35 (s, 2H), 3.15 (t, 2H), 2.98-3.05 (m, 2H), 2.82 (s, 3H), 2.28 (t,2H), 1.40-1.60 (m, 4H), 1.14-1.32 (m, 4H); MS 451 (M+18).

Example 587-{[2′-(1-Hydroxy-hexyl)-biphenyl-4-ylmethyl]-methanesulfonyl-amino}-heptanoicacid

[1213]¹H NMR (CDCl₃ 400 MHz) δ 7.55-7.62 (m, 1H). 7.15-7.45 (m, 7H),4.74 (t, 1H), 4.41 (s, 2H), 3.12-3.28 (m, 2H), 2.88 (s, 3H), 2.30 (t,3H), 1.43-1.75 (m, 6H), 1.05-1.32 (m, 11H), 0.80 (t, 3H); MS 507 (M+18).

Example 59Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide

[1214] Step A: Alkylation

[1215]Trans-N-(6-Cyano-hexyl)-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide

[1216] In an analogous manner to the procedure described in Step A ofExample 1, trans-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide(500 mg, 2.45 mmol) was alkylated with 7-bromoheptanenitrile (781 mg;2.94 mmol) at room temperature over 24 h to provide the title compoundof Step A (760 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.26 (m, 3H), 6.49 (d, 1H),6.22 (m, 1H), 3.98 (m, 2H), 3.22 (t, 2H), 2.88 (s, 3H), 2.36 (t, 2H),1.68-1.35 (m, 8H).

[1217] Step B: Tetrazole Formation

[1218]Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide

[1219] Trimethylsilylazide (0.136 mL, 1.026 mmol) and dibutyltinoxide(38 mg, 0.15 mmol) were added to a solution oftrans-N-(6-cyano-hexyl)-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide(59A) (199 mg, 0.52 mmol) in toluene (4 mL). The reaction was heated atreflux overnight. The reaction was diluted with CH₂Cl₂ and the organicsolution was washed sequentially with HCl (1N, 1×), water (1×), andbrine (1×). The organic solution was dried over MgSO₄, filtered, andconcentrated in vacuo. The product was purified via radialchromatography (CH₂Cl₂ to 5% MeOH/CH₂Cl₂) to afford the title compound(120 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.26 (m, 3H), 6.50 (d, 1H), 6.22 (m,1H), 4.00 (m, 2H), 3.23 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 1.83 (t,2H), 1.62 (t, 2H), 1.38 (m, 4H); MS 132 (M+).

Examples 60-61

[1220] Examples 60-61 were prepared from the appropriate startingmaterials in an analogous manner to Example 59.

Example 60N-(4-Butyl-benzyl)-N-[6-(2H-tetrazol-5-yl)-hexyl]-methanesulfonamide

[1221]¹H NMR (CDCl₃ 400 MHz) δ 7.26-7.17 (m, 4H), 4.36 (s, 2H), 3.17 (t,2H), 3.00 (t, 2H), 2.81 (s, 3H), 2.59 (t, 2H), 1.88 (t, 2H), 1.54 (m,6H), 1.15 (m, 4H), 0.93 (t, 3H); MS 394 (M+1).

Example 61N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide

[1222]¹H NMR (CDCl₃ 400 MHz) δ 6.99 (m, 1H), 6.78 (m, 2H), 4.10 (t, 2H),3.61 (t, 2H), 3.25 (t, 2H), 3.02 (t, 2H), 2.96 (s, 3H), 1.84 (m, 2H),1.64 (m, 2H), 1.40 (m, 4H); MS 436 (M+).

Example 627-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid

[1223] Step A: Reduction

[1224] Ethyl7-[(2′-hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoate

[1225] Sodium borohydride (37 mg, 0.95 mmol) was added to a solution ofethyl 7-{[2′-(1-formyl)-biphenyl-4-ylmethyl]}-heptanoate (415 mg, 0.95mmol) in MeOH (4 mL) at −78° C. The reaction was stirred at −20° C. for1.5 h and water was added. The reaction was diluted with CH₂Cl₂ and theorganic solution was washed with water (1×) and brine (1×). The organicsolution was dried over MgSO₄, filtered, and concentrated in vacuo. Theproduct was purified by flash chromatography (10% EtOAc/hexanes to 50%EtOAc/hexanes) to afford the title compound of Step A (397 mg). ¹H NMR(400 MHz, CDCl₃) δ 7.55-7.62 (m, 1H), 7.23-7.45 (m, 7H), 4.62 (s, 2H),4.42 (s, 2H), 4.09 (q, 2H), 3.20 (t, 2H), 2.89 (s, 3H), 2.26 (t, 2H),1.19-1.70 (m, 11H); MS 465 (M+18).

[1226] Step B: Hydrolysis

[1227]7-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid.

[1228] In an analogous manner to the procedure described in Step B ofExample 1, the title compound of Step A was hydrolyzed to afford thetitle compound (300 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.59 (m, 1H),7.22-7.43 (m, 7H), 4.60 (s, 2H), 4.42 (s, 2H), 3.20 (t, 2H), 2.90 (s,3H), 2.30 (t, 2H), 1.45-1.62 (m, 4H), 1.20-1.30 (m, 4H); MS 437 (M+18).

Example 63 7-(Biphenyl-4-ylmethyl-methanesulfonyl-amino)-heptanoic acid

[1229] Step A: Suzuki Coupling

[1230] Ethyl 7-(Biphenyl-4-ylmethyl-methanesulfonyl-amino)-heptanoate

[1231] Tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.09 mmol),aqueous Na₂CO₃ (0.9 mL, 1M), and phenyl boronic acid (216 mg, 1.77 mmol)were added to a solution of ethyl7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (415 mg, 0.89 mmol)in toluene (37 mL) and EtOH (7 mL). The reaction mixture was heated atreflux for 3 h. The solution was diluted with EtOAc and was washed withwater (2×) followed by brine (1×). The organic solution was dried overMgSO₄, filtered, and concentrated in vacuo. Purification by radialchromatography (10% EtOAc/hexanes to 30% EtOAC/hexanes) provided thetitle compound of Step A (298 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.30(m, 4H), 4.41 (s, 2H), 4.12 (q, 2H), 3.20 (t, 2H), 2.82 (s, 3H), 2.23(t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 418.3 (M+).

[1232] Step B: Hydrolysis

[1233] 7-(Biphenyl-4-ylmethyl-methanesulfonyl-amino)-heptanoic acid

[1234] In an analogous manner to the procedure described in Step B ofExample 1, the title compound of Step A (298 mg, 0.71 mmol) washydrolyzed to afford the title compound (200 mg). ¹H NMR (400 MHz,CDCl₃) δ 7.62-7.30 (m, 9H), 4.42 (s, 2H), 3.20 (t, 2H), 2.87 (s, 3H),2.30 (t, 2H), 1.58 (m, 4H); MS 407 (M+18).

Example 647-[(2′-Formyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

[1235] Step A: Suzuki Coupling

[1236] Ethyl 7-{[2′-(1-formyl)-biphenyl-4-ylmethyl]}-heptanoate

[1237] Tetrakis(triphenyl-phosphine)palladium(0) (85 mg, 0.07 mmol),Na₂CO₃ (0.8 mL, 1M) and 2-formylbenzene boronic acid were added to asolution of ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate(345 mg, 0.74 mmol) in toluene (30 mL) and EtOH (6 mL). After refluxingfor 3 h, the solution was diluted with EtOAc and was washed with water(2×), followed by brine (1×). The organic solution was dried over MgSO₄,filtered, and concentrated in vacuo. The product was purified via radialchromatotography to afford ethyl7-{[2′-(1-formyl)-biphenyl-4-ylmethyl]}-heptanoate (320 mg). ¹H NMR (400MHz, CDCl₃) δ 9.95 (s, 1H), 8.05 (d, 1H), 7.35-7.70 (m, 7H), 4.46 (s,2H), 4.10 (q, 2H), 3.19-3.28 (m, 2H), 2.90 (s, 3H), 2.28 (t, 2H),1.50-1.62 (m, 5H), 1.20-1.35 (m, 6H); MS 463 (M+18).

[1238] Step B: Hydrolysis

[1239]7-[(2′-Formyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

[1240] In an analogous manner to the procedure described in Step B ofExample 1, ethyl 7-{[2′-(1-formyl)-biphenyl-4-ylmethyl]}-heptanoate (75mg, 0.172 mmol) was hydrolyzed to afford the title compound (55 mg). ¹HNMR (400 MHz, CDCl₃) δ 9.93 (s, 1H), 8.04 (d, 1H), 7.63 (m, 1H),7.52-7.37 (m, 6H), 4.43 (s, 2H), 3.22 (t, 2H), 2.91 (s, 3H), 2.32 (t,2H), 1.56 (m, 4H), 1.30 (m, 4H).

Example 657-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoicacid

[1241] Step A: Suzuki Coupling

[1242] Ethyl7-{[4-(3-formyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoate

[1243] Tetrakis(triphenylphosphine)palladium(0) (91 mg, 0.08 mmol),Na₂CO₃ (0.87 mL, 1M) and 5-formyl-2-thiopheneboronic acid (247 mg, 1.58mmol) were added to a solution of ethyl7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (371 mg, 0.79 mmol)in toluene (33 mL) and EtOH (6.5 mL). The reaction mixture was heated atreflux for 3 h. The solution was diluted with EtOAc and the organicsolution was washed with water (2× followed by brine (1×). The organicsolution was dried over MgSO₄, filtered, and concentrated in vacuo. Theproduct was purified via radial chromatography (25% EtOAc/hexanes to 50%EtOAc/hexanes) to afford the title compound of Step A (75 mg). ¹H NMR(400 MHz, CDCl₃) δ 9.89 (s, 1H), 7.44-7.60 (m, 5H), 7.21-7.31 (m, 1H),4.45 (s, 2H), 4.10 (q, 2H), 3.20 (t, 2H), 2.90 (s, 3H), 2.25 (t, 3H),1.58 (m, 4H), 1.35 (m, 7H); MS 452 (M+).

[1244] Step B: Reduction

[1245] Ethyl7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoate

[1246] Sodium borohydride (6.0 mg, 0.16 mmol) was added to a solution ofthe title compound of Step A (70 mg, 0.16 mmol) in MeOH (1 mL) at −78°C. The reaction was stirred at −20° C. for 2 h and water was added. Themixture was diluted with CH₂Cl₂ and the organic solution was washed withwater (1×) and brine (1×). The organic solution was dried over MgSO₄,filtered, and concentrated in vacuo to afford 65B (62 mg) which was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.52 (m,6H), 4.68 (s, 2H), 4.40 (s, 2H), 4.09 (q, 2H), 3.19 (t, 2H), 2.86 (s,3H), 2.24 (t, 2H), 1.82 (bs, 1H), 1.18-1.60 (m, 11H).

[1247] Step C: Hydrolysis

[1248]7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]methanesulfonyl-amino}-heptanoicacid

[1249] In an analogous manner to the procedure described in Step B ofExample 1, the title compound of Step B (60 mg, 0.13 mmol) washydrolyzed to afford the title compound (29 mg). ¹H NMR (400 MHz, CDCl₃)δ 7.15-7.52 (m, 7H), 4.68 (s, 2H), 4.40 (s, 2H), 3.19 (t, 2H), 2.88 (s,3H), 2.30 (t, 2H), 1.52 (m, 4H), 1.33 (m, 4H); MS 443 (M+18).

Example 66 7-[(4-Hexanoyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

[1250] A solution of7-{[4-(1-hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic acid(88 mg, 0.21 mmol) and Dess-Martin reagent (145 mg, 0.34 mmol) in CH₂Cl₂(2 mL) was stirred at room temperature for 72 h. Sodium thiosulfatesolution was added and the reaction mixture was stirred until all solidswere dissolved. The aqueous layer was extracted with CH₂Cl₂ (2×), andthe organic solution was dried over MgSO₄, filtered, and concentrated invacuo. Purification by radial chromatography (CH₂Cl₂to 5% MeOH/CH₂Cl₂)provided the title compound (93.6 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.92(d, 2H), 7.43 (d, 2H), 4.40 (s, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 2.85(s, 3H), 2.28 (t, 2H), 1.71 (m, 2H), 1.50 (m, 4H), 1.15-1.40 (m, 8H),0.85-0.95 (m, 3H).

Example 67(4-{2-[(4-Butyl-benzyl)-methanesulfonyl-amino]-ethyl}-phenyl)-aceticacid

[1251] Step A: Alkylation

[1252](4-{2-[(4-Butyl-benzyl)-methanesulfonyl-amino]-ethyl}-phenyl)-aceticacid methyl ester

[1253] A mixture of [4-[2-methanesulfonylamino-ethyl]-phenyl]-aceticacid methyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35mg, 0.15 mmol), K₂CO₃ (25 mg, 0.182 mmol) and acetonitrile was heated atreflux for 1 h. Aqueous HCl (2 mL, 1N) and EtOAc (30 mL) were added tothe reaction. The organic solution was dried with MgSO₄, filtered, andconcentrated in vacuo. The product was purified by flash chromatography(30% EtOAc/hexanes) to afford the title compound of Step A. ¹H NMR (400MHz, CDCl₃) δ 7.28-7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s,2H), 3.26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m,2H), 1.37 (m, 2H), 0.94 (t, 3H).

[1254] Step B: Hydrolysis

[1255](4-{2-[(4-Butyl-benzyl)-methanesulfonyl-amino]-ethyl}-phenyl)-aceticacid

[1256] In an analogous manner to Step B of Example 1, the title compoundof Step A was hydrolyzed to provide the title compound. ¹H NMR (400 MHz,CDCl₃) 7.15 (m, 8H), 4.35 (s, 2H), 3.66 (s, 2H), 3.35 (t, 2H), 2.75 (t,2H), 2.65 (s, 3H), 2.59 (m, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.91 (t,3H).

Example 687-[[4-(1-Hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid

[1257] Step A: Reductive Amination

[1258] 7-Methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate

[1259] A solution of 7-aminoheptanoic methyl ester hydrochloride (1.57g, 8.02 mmol), 4-(1-hydroxy-hexyl)-benzaldehyde (1.98 g, 9.63 mmol),sodium acetate (1.32 g, 16.05 mmol) and NaBH₃CN (605 mg, 9.63 mmol) inMeOH (50 mL) was stirred at room temperature for 24 h. The reactionmixture was concentrated in vacuo and was diluted with EtOAc. Thesolution was washed sequentially with NaHCO₃ (1×), water (1×), and brine(1×). The organic solution was dried over MgSO₄, filtered, andconcentrated in vacuo. The product was purified by flash chromatography(1% MeOH/CHCl₃ to 5% MeOH/CHCl₃) to afford7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate (1.28 g).

[1260] Step B: Amide Formation

[1261]7-[[4-(1-Hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid methyl ester

[1262] A solution of7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate (82.2 mg, 0.235mmol), 1-propanesulfonyl chloride (29.1 μL, 0.259 mmol) and4-methylmorpholine (28.5 μL, 0.259 mmol) in CH₂Cl₂ (10 mL) was stirredat room temperature for 24 h. Additional 1-propanesulfonyl chloride(14.5 μL) and 4-methylmorpholine (14.3 μL) were added, and the reactionwas stirred for 5 days. The organic solution was washed consecutivelywith 5.5% HCl, water, aqueous NaHCO₃, and brine. The organic solutionwas dried (MgSO₄), filtered, and concentrated to yield7-[[4-(1-hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid methyl ester which was used in the next step without furtherpurification.

[1263] Step C: Hydrolysis

[1264]7-[[4-(1-Hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid

[1265] In analogous manner to the procedure described in Step B ofExample 1,7-[[4-(1-hydroxy-hexyl)-benzyl]-(propane-1-sulfonyl)-amino]-heptanoicacid methyl ester was hydrolyzed at room temperature over 24 h to affordthe title compound (43 mg) as an oil. ¹H NMR (400 MHz, CDCl₃) δ7.35-7.22 (d, 2H), 7.11-7.00 (d, 2H), 4.61 (q, 1H), 4.50 (s, 2H), 3.31(t, 2H), 2.40-2.20 (m, 4H), 2.81-1.43 (m, 10H), 1.41-1.22 (m, 8H),1.31-0.81 (m, 6H); MS 440 (M−1).

Example 69

[1266] Example 69 was prepared from the appropriate starting materialsin an analogous manner to Example 68.

Example 697-[Methanesulfonyl-(4-phenyl-thiophen-2-ylmethyl)-amino]-heptanoic acid

[1267]¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, 1H), 7.40-7.20 (m, 6H), 4.65(s, 2H), 3.20 (t, 2H), 3.02 (s, 3H), 2.25 (t, 2H), 1.60 (m, 4H), 1.25(m, 4H); MS 394 (M−1).

Example 70 7-{[4-(1-Hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoicacid

[1268] Step A: Amide Formation

[1269]7-Methyl-{[4-(1-hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoate

[1270] A solution of7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoate (314 mg, 0.90mmol), propionic acid, (73.02 mg, 0.99 mmol), and DCC (203.6 mg, 0.99mmol) in CH₂Cl₂ (20 mL) was stirred at room temperature for 24 h. Thesolids were removed via filtration and the filtrate was concentrated invacuo. EtOAc was added to the residue and the insolubles were removed byfiltration. The organic solution was washed consecutively with aqueousHCl (5.5%, 1×), water (1×), aqueous NaHCO₃ (1×), and brine (1×). Theorganic solution was dried (MgSO₄), filtered, and concentrated to afford7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoate (403mg) as an oil which was used without further purification.

[1271] Step B: Hydrolysis

[1272] 7-{[4-(1-Hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoic acid

[1273] In an analogous manner to the procedure described in Step B ofExample 1,7-methyl-{[4-(1-hydroxy-hexyl)-benzyl]-propionyl-amino}-heptanoate (365mg, 0.90 mmol) was hydrolyzed at room temperature over 24 h to affordthe title compound (254 mg) as an oil. ¹H NMR (300 MHz, CDCl₃) δ7.33-7.11 (m, 4H), 4.43-4.66 (m, 3H), 3.33 (t, 1H), 3.17 (t, 1H),2.25-2.47 (m, 4H), 1.02-1.87 (m, 19H), 0.86 (m, 3H); MS 391.4 (M+).

Examples 71-72

[1274] Examples 71-72 were prepared from the appropriate startingmaterials in an analogous manner to Example 70.

Example 71 7-{Butyryl-[4-(1-hydroxy-hexyl)-benzyl]-amino}-heptanoic acid

[1275]¹H NMR (300 MHz, CDCl₃) δ 7.32-7.21 (d, 2H), 7.15-7.02 (d, 2H),4.60 (q, 1H), 4.40 (s, 2H), 3.22 (t, 2H), 2.70 (t, 2H), 2.41-2.20 (t,2H), 1.85-1.55 (m, 10H), 1.45-1.22 (m, 8H), 1.01-0.85 (m, 6H); MS 404(M−1).

Example 72 7-[(4-Butyl-benzyl)-propionyl-amino]-heptanoic acid

[1276]¹H NMR (300 MHz, CDCl₃) δ 7.32-7.21 (d, 2H), 7.10-7.00 (d, 2H),4.50 (s, 2H), 3.30 (t, 2H), 2.50 (m, 2H), 2.32 (m, 4H), 1.50 (m, 4H),1.22 (m, 8H), 1.20 (t, 3H), 0.95 (t, 3H); MS 348 (M+).

Example 73 7-[Methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid

[1277] Step A: Alkylation

[1278] Trans-7-[Methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acidethyl ester

[1279] In an analogous manner to the procedure described in Step A ofExample 1, ethyl-7-amino-heptanoate (502 mg, 2 mmol) was alkylated withtrans-4-chloromethylstilbene (502.7 mg, 2.2 mmol) at room temperatureover 24 h to providetrans-7-[methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethylester (0.90 g). ¹H NMR (400 MHz, CDCl₃) δ 7.50 (m, 4H), 7.40-7.20 (m,5H), 7.10 (m, 2H), 4.36 (s, 2H), 4.09 (q, 2H), 3.15 (t, 2H), 2.81 (s,3H), 2.22 (t, 2H), 1.54 (m, 4H), 1.15-1.32 (m, 7H).

[1280] Step B: Hydrogenation

[1281] 7-[Methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acidethyl ester

[1282] A solution oftrans-7-[methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethylester (0.60 g) in MeOH (5 mL) and EtOAc (50 mL) was added to 10%Pd/carbon (0.2 g). The reaction mixture was placed on a Parrhydrogenator and was hydrogenated for 20 h at 50 psi. The reactionmixture was filtered through celite and concentrated in vacuo to afford7-[methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid ethylester (0.60 g). ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.10 (m, 9H), 4.32 (s,2H), 4.10 (q, 2H), 3.12 (t, 2H), 2.90 (s, 4H), 2.79 (s, 3H), 2.25 (t,2H), 1.60-1.45 (m, 4H), 1.30-1.19 (m, 7H).

[1283] Step C: Ester Hydrolysis

[1284] 7-[Methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid

[1285] In an analogous manner to the procedure described in Step B ofExample 1, 7-[methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acidethyl ester (600 mg) was hydrolyzed to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.30-7.10 (m, 9H), 4.32 (s, 2H), 3.13 (t, 2H), 2.91(s, 4H), 2.79 (s, 3H), 2.30 (t, 2H), 1.61-1.47 (m, 4H), 1.32-1.18 (m,4H).

Example 74Trans-4-{2-[Methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acid

[1286] Step A: Alklation

[1287]Trans-4-{2-[Methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acidmethyl ester

[1288] To a solution of 4-(2-methanesulfonylamino-ethoxy)-benzoic acidmethyl ester (62 mg, 0.23 mmol) in DMF (10 mL) at 0° C. was added sodiumbis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL, 0.24 mmol) dropwise.After 20 minutes, cinnamyl bromide (51 mg, 0.26 mmol) was added and thereaction was stirred at room temperature for 2 h. Aqueous 1N HCl wasadded and the product was extracted into EtOAc. The organic solution waswashed with 1N HCl (3×) followed by brine. The organic solution wasdried (Na₂SO₄), filtered, and concentrated. Radial chromatography (20%EtOAc in hexanes) providedtrans-4-{2-[methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acidmethyl ester (70 mg). ¹NMR (400 MHz, CDCl₃) δ 7.97 (d, 2H), 7.35-7.23(m, 5H), 6.88 (d, 2H), 6.58 (d, 1H), 6.18 (m, 1H), 4.20 (t, 2H), 4.12(d, 2H), 3.88 (s, 3H), 3.68 (t, 2H), 2.95 (s, 3H).

[1289] Step B: Hydrolysis

[1290]Trans-4-{2-[Methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acid

[1291] In an analogous manner to the procedure described in Step B ofExample 1,trans-4-{2-[methanesulfonyl-(3-phenyl-allyl)-amino]-ethoxy}-benzoic acidmethyl ester (60 mg) was hydrolyzed to provide the title compound (35mg). ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, 2H), 7.30 (m, 5H), 6.92 (d, 2H),6.60 (d, 1H), 6.19 (m, 1H), 4.24 (t, 2H), 4.15 (d, 2H), 3.71 (t, 2H),2.98 (s, 3H); MS 375 (M+).

Preparation A1 N-(4-Butyl-benzyl)-methanesulfonamide

[1292] Step A: Nitrile Reduction

[1293] 4-Butylbenzylamine. A solution of 4-butylbenzonitrile (3.63 g,22.8 mmol) in THF (10 mL) was placed in a three-neck round bottom flaskequipped with a vigreux column and short-path distillation head. Thesolution was heated to reflux and BH₃-methyl sulfide complex (2.0 M inTHF, 15 mL, 30 mmol) was added dropwise over 15 minutes. Methyl sulfidewas distilled off from the reaction mixture over 1 h and the solutionwas cooled to room temperature. Aqueous HCl (6N, 25 mL) was added slowlyvia an addition funnel and the mixture was heated at reflux for 30minutes. The reaction was cooled to 0° C. and NaOH (7.0 g) was addedportionwise. The aqueous solution was extracted with EtOAc (3×) and theorganic solution was dried (MgSO₄), filtered, and concentrated. Theproduct (4.01 g) was used in the next step without further purification.¹H NMR (400 MHz, CDCl₃) δ 7.34 (m, 2H), 7.24 (m, 2H), 4.04 (s, 2H), 2.62(t, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).

[1294] Step B: Sulfonamide Formation

[1295] To a solution of 4-butylbenzylamine (4.01 g, 24.6 mmol) in CH₂Cl₂(75 mL) was added pyridine (4.0 mL, 49 mmol) followed by dropwiseaddition of methanesulfonyl chloride (2.5 mL, 32.3 mmol). The reactionwas stirred at room temperature for 24 h and water was added. Theproduct was extracted into CH₂Cl₂ (2×) and the organic solution wasdried (MgSO₄), filtered, and concentrated. Flash chromatography (2:1 to1:1 hexanes:EtOAc) provided the title compound as a white solid (3.4114g). ¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, 2H), 7.15 (d, 2H), 4.84 (m, 1H),4.25 (d, 2H), 2.82 (s, 3H), 2.58 (t, 2H), 1.56 (m, 2H), 1.33 (m, 2H),0.91 (t, 3H).

[1296] In an analogous manner, the following compounds were preparedfrom the appropriate starting materials using the above generalprocedure of Preparation A1.

Preparation A2 N-[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonamidePreparation A3 N-[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonamidePreparation A4 4-Iodobenzyl-methanesulfonamide

[1297] The title compound was prepared from 4-iodobenzylamine in ananalogous manner to step B of Preparation A1. ¹H NMR (400 MHz, CDCl₃) δ7.69 (d, 2H), 7.10 (d, 2H), 4.82 (bs, 1H), 4.28 (d, 2H), 2.87 (s, 3H).

Preparation A5 N-[3-(2-Chloro-phenyl)-propyl]-methanesulfonamidePreparation B1 Ethyl7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate.

[1298] In an analogous manner to the procedure described in Step A ofExample 1, 4-iodobenzyl-methanesulfonamide (2.67 g, 8.59 mmol) wasalkylated with ethyl-7-bromoheptanoate (2.00 g, 8.44 mmol) at 50° C. for2 h and at room temperature for 24 h to provide the title compound (3.61g). ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, 2H), 7.12 (d, 2H), 7.31 (s, 2H),4.12 (q, 2H), 3.13 (t, 2H), 2.83 (s, 3H), 2.27 (t, 2H), 1.42-1.65 (m,5H), 1.15-1.35 (m, 6H); MS 468 (M+).

[1299] In an analogous manner, the following compounds were preparedfrom the appropriate starting materials using the above generalprocedure of Preparation B1 with variations in reaction temperature andtime as indicated.

Preparation B2 7-(Allyl-methanesulfonyl-amino)-heptanoic acid ethylester

[1300] As described in Preparation B1: 24 h at room temperature. ¹H NMR(400 MHz, CDCl₃) δ 5.71-5.81 (m, 1H), 5.16-5.24 (m, 2H), 4.01-4.10 (m,2H), 3.70-3.80 (m, 2H), 3.07-3.15 (m, 2H), 2.77 (s, 3H), 2.21 (t, 2H),1.47-1.58 (m, 4H), 1.22-1.34 (m, 4H), 1.18 (t, 3H).

Preparation B3 7-(But-3-enyl-methanesulfonyl-amino)-heptanoic acid ethylester

[1301] As described in Preparation B1: 90° C. for 24 h.

Preparation B4 N-(6-Cyano-hexyl)-methanesulfonamide

[1302] As described in Preparation B1: 90° C. for 24 h. ¹H NMR (400 MHz,CDCl₃) δ 4.24 (m, 1H), 3.11 (q, 2H), 2.83 (s, 3H), 2.35 (t, 2H),1.70-1.37 (m, 8H); MS 222 (M+18).

Preparation C1 5-(3-Methanesulfonylamino-propyl)-thiophene-2-carboxylicacid methyl ester

[1303] Step A

[1304] 5-(3-Methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylicacid methyl ester. To a solution of 5-bromo-thiophene-2-carboxylic acidmethyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09g, 8.2 mmol), Et₃N (1.7 mL, 12.1 mmol), and CH₃CN (30 mL) was addedPd(PPh₃)₄ (462 mg, 0.4 mmol) followed by CuI (76 mg, 0.4 mmol). Thereaction was heated at reflux for 24 h and was cooled to roomtemperature. The volatiles were removed in vacuo and the residue waspurified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc inhexanes) to yield5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidmethyl ester as a pale yellow solid (1.1 g). ¹H NMR (300 MHz, CDCl₃) δ7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H),3.10 (s, 3H); MS 274 (M+1).

[1305] Step B: Hydrogenation

[1306] A solution of5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidmethyl ester (3.0 g, 10.9 mmol) in EtOAc (100 mL) and MeOH (50 mL) washydrogenated with 10% Pd/C (680 mg) at 50 psi for 7 h. The solution wasfiltered through a pad of Celite with the aid of MeOH and wasconcentrated in vacuo to provide the title compound as an off-whitesolid (2.95 g). ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, 1H), 7.23 (d, 1H),4.29 (m, 1H), 3.85 (s, 3H), 3.18 (q, 2H), 2.93 (m, 5H), 1.96 (m, 2H).

[1307] In an analogous manner, the following compounds were preparedfrom the appropriate starting materials using the above generalprocedure of Preparation C1.

Preparation C2 N-[3-(3-Chloro-phenyl)-propyl]-methanesulfonamidePreparation C3N-[3-(3-Trifluoromethyl-phenyl)-propyl]-methanesulfonamide PreparationD1 1-Bromomethyl-4-butyl-benzene

[1308] HBr was bubbled into a solution of (4-butyl-phenyl)-methanol(10.0 g, 60.9 mmol) in CH₂Cl₂ (100 mL) for 15 minutes. The reaction wasstirred for an additional 45 minutes and was poured onto ice water. Theaqueous solution was extracted with CH₂Cl₂ (2×) and was dried (MgSO₄),filtered, and concentrated to provide the title compound which was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (d, 2H),7.14 (d, 2H), 4.49 (s, 2H), 2.60 (t, 2H), 1.58 (m, 2H), 1.36 (m, 2H),0.92 (t, 3H).

[1309] In an analogous manner, the following compound was prepared fromthe appropriate starting materials using the general procedure ofPreparation D1.

Preparation D2 1-Bromomethyl-4-isopropyl-benzene

[1310]¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, 2H), 7.19 (d, 2H), 4.49 (s,2H), 2.90 (m, 1H), 1.24 (d, 6H).

Preparation E1 4′-Bromomethyl-2-chloro-biphenyl

[1311] Step A: Suzuki Coupling

[1312] 4′-Methyl-2-chloro-biphenyl.Tetrakis(triphenylphosphine)palladium(0) (637 mg, 0.551 mmol), Na₂CO₃ (5mL, 1M) and 4-methylbenzene boronic acid (1.5 g, 11.0 mmol) were addedto a solution of 2-chloroiodobenzene (1.315 g, 5.514 mmol) in toluene(98 mL) and EtOH (20 mL). The reaction mixture was heated at reflux for3 h. The cooled solution was diluted with EtOAc, and the organicsolution was washed with water (2×) followed by brine (1×). The organicsolution was dried over MgSO₄, filtered, and concentrated in vacuo. Theproduct was purified by flash chromatography (hexanes to 10%EtOAC/hexanes) to afford 4′-methyl-2-chloro-biphenyl (1.08 g). ¹H NMR(CDCl₃ 400 MHz) δ 7.49-7.21 (m, 8H), 2.39 (s, 3H).

[1313] Step B: Benzylic Bromination

[1314] A mixture of 4′-methyl-2-chloro-biphenyl (1.08 g, 5.33 mmol), NBS(1.14 g, 6.40 mmol) and AlBN (175 mg, 1.06 mmol) in CCl₄ (37 mL) washeated at reflux for 3 h. The reaction mixture was diluted with CH₂Cl₂and the organic solution was washed sequentially with aqueous saturatedNaHCO₃ (2×), water (1×), and brine (1×). The organic solution was driedover MgSO₄, filtered, and concentrated in vacuo. The product waspurified by flash chromatography (hexanes to 5% EtOAc/hexanes) to affordthe title compound (920 mg). ¹H NMR (CDCl₃ 400 MHz) δ 7.63-7.25 (m, 8H),4.56 (s, 2H).

[1315] In an analogous manner, the following compounds were preparedfrom the appropriate starting materials using the above generalprocedure of Preparation E1.

Preparation E2 4′-Bromomethyl-2-trifluoromethyl-biphenyl Preparation E34′-Bromomethyl-2,6-dichloro-biphenyl Preparation F1(3-Bromomethyl-phenyl)-acetic acid methyl ester

[1316] A solution of m-tolyl-acetic acid methyl ester (11.41 g, 69.49mmol), N-bromosuccinimide (12.59 g, 70.73 mmol), AlBN (100 mg) in CCl₄(200 mL) was heated at reflux for 16 h. The reaction was cooled to roomtemperature and aqueuos NaHCO₃ (satd) was added. The aqueous solutionwas extracted with CH₂Cl₂ (2×) and the organic solution was dried(MgSO₄), filtered, and concentrated. Purification by flashchromatography (hexanes to 9:1 hexanes:EtOAc) provided the titlecompound as a clear and colorless liquid (11.99 g). ¹H NMR (CDCl₃ 400MHz) δ 7.27 (m, 4H), 4.47 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H).

[1317] In an analogous manner, the following compound was prepared fromthe appropriate starting materials using the above general procedure ofPreparation F1).

Preparation F2 2-(4-Bromomethyl-phenyl)-pyridine Preparation G14-[(1-Acetyloxy)-hexyl]-benzyl bromide

[1318] Step A: Grignard Reaction and Protection

[1319] 4-[(1-Acetyloxy)-hexyl]-toluene. Pentylmagnesium bromide (2.0 Min Et₂O, 25 mL, 50 mmol) was added slowly to p-tolylbenzaldehyde (5.0mL, 42.4 mmol) in THF (50 mL) at 0° C. The reaction was warmed to roomtemperature and was stirred for 3 h. Aqueous 1N HCl was added and theaqueous solution was extracted with EtOAc. The organic solution waswashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was dissolved in pyridine (35 mL) and Ac₂O (10 mL) was added.The reaction was stirred for 24 h and was diluted with water. Theproduct was extracted into EtOAc (3×) and the organic solution waswashed with 1N HCl followed by brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (10%EtOAc/hexanes) to afford 4-[(1-acetyloxy)-hexyl]-toluene (2.082 g). ¹HNMR (400 MHz, CDCl₃) δ 7.12-7.28 (m, 4H), 5.69 (t, 1H), 2.33 (s, 3H),2.04 (s,3H), 1.88 (m, 1H), 1.74 (m, 1H), 1.27 (m, 6H), 0.86 (m, 3H); MS252 (M+18).

[1320] Step B: Benzylic Bromination

[1321] A mixture of 4-[(1-acetyloxy)-hexyl]-toluene (2.082 g, 8.89mmol), NBS (1.58 g, 8.89 mmol), and catalytic AlBN in CCl₄ (30 mL) washeated at reflux for 2 h. The reaction was cooled and was washed withaqueous NaHCO₃ (satd), dried over MgSO₄, filtered, and concentrated. Theproduct was purified by flash chromatography (5% EtOAc/hexanes) toafford the title compound (2.67 g). ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.40(m, 4H), 5.70 (t, 1H), 4.47 (s, 2H), 2.06 (s, 3H), 1.86 (m, 1H), 1.73(m, 1H), 1.27 (m, 6H), 0.85 (m, 3H).

[1322] In an analogous manner, the following compound was prepared fromthe appropriate starting materials using the above general procedure ofPreparation G1.

Preparation G2 Acetic acid 1-(5-bromomethyl-thiophen-2-yl)-hexyl esterPreparation H1 Trans-1-(3-Bromo-propenyl)-3,5-dichloro-benzene

[1323] Step A: Grignard Reacton

[1324] 1-(3,5-Dichloro-phenyl)-prop-2-en-1-ol. A solution of3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 mL) was cooled to0° C. and vinylmagnesium bromide (1M in THF, 48 mL, 48 mmol) was addeddropwise. The reaction was warmed to room temperature and was stirredovernight. Aqueous HCl (1N) and EtOAc were added. The aqueous solutionwas extracted with EtOAc and the organic solution was dried (MgSO₄),filtered, and concentrated. The residue was used in the next stepwithout further purification.

[1325] Step B: Bromination

[1326] The residue prepared in Step A was dissolved in Et₂O and HBr gaswas slowly bubbled into the solution for about 15 minutes. The reactionwas stirred at room temperature for 24 h and water and EtOAc were added.The aqueous solution was extracted with EtOAc and the organic solutionwas dried (MgSO₄), filtered, and concentrated. Purification by flashchromatography (hexanes) provided the title compound (6.91 g). ¹H NMR(400 MHz, CDCl₃) δ 7.24 (s, 3H), 6.53 (d, 1H), 6.40 (m, 1H), 4.10 (m,2H).

[1327] In an analogous manner, the following compound was prepared fromthe appropriate starting materials using the above general procedure ofPreparation H1.

Preparation H2 Trans-1-(3-Bromo-propenyl)-3,5-difluoro-benzene

[1328]¹H NMR (400 MHz, CDCl₃) δ 6.83-6.95 (m, 2H), 6.65-6.75 (m, 1H),6.55 (d, 1H), 6.34-6.45 (m, 1H), 4.10 (d, 2H).

Preparation I1 4-Isobutylbenzylbromide

[1329] Step A: Reduction

[1330] (4-Isobutyl-phenyl)-methanol. A solution of lithium aluminumhydride (30 mL, 1M in THF, 30 mmol) was added dropwise to a solution of4-isobutylbenzoic acid (5.34 g, 30 mmol) in THF (50 mL) at 0° C. The icebath was removed and the reaction was stirred at room temperature for 1h. The reaction was carefully poured onto a mixture of ice and aqueousHCl (10 mL, 6N). The product was extracted into EtOAc and the organicsolution was dried (MgSO₄), filtered, and concentrated to obtain(4-isobutyl-phenyl)-methanol which was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, 2H), 7.13 (d,2H), 4.65 (s, 2H), 2.46 (d, 2H), 1.85 (m, 1H), 0.89 (d, 6H).

[1331] Step B: Bromination

[1332] HBr gas was bubbled through a solution of(4-isobutyl-phenyl)-methanol (5 g, 28 mmol) in Et₂O (50 mL) for 10-15minutes. The reaction was stirred for 1 h and was poured onto ice (100g). Et₂O was added and the organic solution was washed with brine (2×).The organic solution was dried (MgSO₄), filtered, and concentrated toprovide the title compound (6 g). ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d,2H), 7.10 (d, 2H), 4.49 (s, 2H), 2.45 (d, 2H), 1.84 (m, 1H), 0.89 (d,6H).

[1333] In an analogous manner, the following compound was prepared fromthe appropriate starting materials using the above general procedure ofPreparation I1.

Preparation I2 1-(Bromomethyl)-4-(phenylmethyl)-benzene Preparation J17-[(4-Formyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

[1334] Step A

[1335] 1-Bromomethyl-4-vinyl-benzene. Bromine (16.4 g, 103 mmol) wasslowly added to a solution of triphenylphosphine (28.87 g, 110.1 mmol)in CH₂Cl₂ (260 mL) at 0° C. After 10 minutes, 4-vinylbenzyl alcohol(12.5 g, 93.3 mmol) was added and the reaction mixture was stirred at 0°C. for 2 h. The reaction mixture was washed with water (1×) followed bybrine (1×). The organic solution was dried over MgSO₄, filtered, andconcentrated in vacuo. The product was triturated with petroleum ether(3×), and the ethereal solution was concentrated in vacuo. The residuewas purified by flash chromatography (hexanes) to afford 4-vinyl-benzylbromide (6.23 g). ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.45 (m, 4H), 6.72 (dd,1H), 5.77 (d, 1H), 5.28 (d, 1H), 4.50 (s, 2H).

[1336] Step B: Alkylation

[1337] Ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate.According to the procedure described in Preparation B1,ethyl-7-methanesulfonyl-amino-heptanoate (2.30 g, 9.02 mmol) wasalkylated with 4-vinylbenzyl bromide (1.77 g, 9.02 mmol) over 3 h atroom temperature to provide, after flash chromatography chromatography(10% EtOAc/hexanes to 50% EtOAc/hexanes),ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.21 g). ¹HNMR (400 MHz, CDCl₃) δ 7.23-7.45 (m, 4H), 6.72 (dd, 1H), 5.76 (d, 1H),5.28 (d, 1H), 4.38 (s, 2H), 4.12 (q, 2H), 3.14 (t, 2H), 2.83 (s, 3H),2.24 (t, 2H), 1.15-1.64 (m, 11H); MS 385 (M+18).

[1338] Step C: Oxidation

[1339] A solution ofethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholineN-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL,2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirredat room temperature for 1 h. The reaction was quenched with 1N HCl (50mL) and the aqueous solution was extracted with CH₂Cl₂. The organiclayer was washed with water (1×) followed by brine (1×), dried overMgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in35% aqueous THF (100 mL) and NaIO₄ (1.41 g, 6.59 mmol) was added. Themixture was stirred at room temperature for 2 h and was diluted withEtOAc and water. The organic solution was washed with water (1×)followed by brine (1×), dried over MgSO₄, filtered, and concentrated invacuo to afford the title compound (1.9 g) which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 10.0 (s, 1H), 7.82-7.90(d, 1H), 7.50-7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.05-4.18 (m,2H), 3.12-3.22 (m, 2H), 2.86 (s, 3H), 2.19-2.30 (m, 2H), 1.42-1.62 (m,6H), 1.18-1.30 (m, 3H); MS 387 (M+18).

Preparation K1 (4-Methanesulfonylamino-butoxy)-acetic acid ethyl ester

[1340] Step A: Alkylation

[1341] (4-Bromo-butoxy)-acetic acid ethyl ester. A solution of ethylglycolate (4.6 g, 44 mmol) in DMF (50 mL) was cooled to 0° C. and sodiumbis(trimethylsilyl)amide (1.0 M in THF, 53 mL, 53 mmol) was slowlyadded. The reaction was stirred for 15 minutes and 1,4-dibromobutane(5.6 mL, 48.4 mmol) was added. The reaction was warmed to roomtemperature and was stirred for 24 h. Et₂O was added, and the organicsolution was washed consecutively with HCl (1N, 3×), water (3×), andbrine (1×). The organic solution was dried (Na₂SO₄), filtered, andconcentrated. Attempted vacuum distillation removed a majority of theimpurities and provided a mixture of product and 1,4-dibromobutane(3.539 g). Flash chromatography (9:1 hexanes:EtOAc) of this materialprovided (4-bromo-butoxy)-acetic acid ethyl ester (1.862 g). ¹H NMR (400MHz, CDCl₃) δ 4.19 (q, 2H), 4.04 (s, 2H), 3.54 (t, 2H), 3.45 (t, 2H),1.97 (m, 2H), 1.75 (m, 2H), 1.26 (t, 3H); MS 239.1 (M+).

[1342] Step B: Alkylation

[1343] To a mixture of NaH (60% in oil, 167 mg, 4.18 mmol) and DMF (10mL) was added a solution of methanesulfonamide (398 mg, 4.18 mmol) inDMF (5 mL). The mixture was heated at 100° C. for 1.5 h and was cooledto room temperature. A solution of (4-bromo-butoxy)-acetic acid ethylester (1.000 g, 4.182 mmol) in DMF (10 mL) was added and the reactionwas heated at 100° C. for 21 h. Water was added to the cooled reactionmixture and the aqueous solution was acidified to pH=2 with concentratedHCl. The aqueous solution was extracted with EtOAc (4×) and the organicsolution was dried (MgSO₄), filtered, and concentrated. The product waspurified by flash chromatography (60% EtOAc/hexanes) to afford the titlecompound (181 mg). ¹H NMR (400 MHz, CDCl₃) δ 4.90 (m, 1H), 4.20 (q, 2H),4.04 (s, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.93 (s, 2H), 1.69 (m, 4H),1.26 (t, 3H); MS 254.1 (M+1).

Preparation L1 1-(2-Bromo-ethoxy)-3,5-dichloro-benzene

[1344] To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) wasadded 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated atreflux for 1 h and was cooled to room temperature. Dibromoethane (11.52g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h.The cooled solution was diluted with EtOAc and the organic solution waswashed sequentially with HCl (1N, 1×), water (1×), and brine (1×). Theorganic solution was dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography (hexanes to 5% EtOAc in hexanes)provided the title compound (3.79 g). ¹H NMR (400 MHz, CDCl₃) δ 6.98 (m,1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).

[1345] In an analogous manner, the following compounds were preparedfrom the appropriate starting materials using the above generalprocedure of Preparation L1.

Preparation L2 1-(2-Bromo-ethoxy)-3,5-dimethyl-benzene Preparation L31-(2-Bromo-ethoxy)-3,5-dimethoxy-benzene Preparation M14-(1-Hydroxy-hexyl)-benzaldehyde

[1346] A solution of 4-diethoxymethyl-benzaldehyde (0.300 mL, 1.51 mmol)in THF (3 mL) was cooled to 0° C. Pentylmagnesium bromide (3.0 mL, 2.0 Min THF, 6 mmol) was added dropwise. The reaction was stirred at 0° C.for 1 h and was warmed to room temperature. Aqueous NH₄Cl (satd) wasadded and the aqueous solution was extracted with EtOAc. The organicsolution was washed with brine, dried (MgSO₄), filtered, andconcentrated. The residue was dissolved in 10% aqueous acetone (50 mL)and wet Amberlyst-15 resin (1.5 g) was added. The mixture was stirredfor 24 h and the resin was filtered off through Celite. The solution wasconcentrated in vacuo. Purification via flash chromatography (4:1hexanes:EtOAc) provided the title compound (1.15 g). ¹H NMR (400 MHz,CDCl₃) δ 9.99 (s, 1H), 7.86 (d, 2H), 7.51 (d, 2H), 4.77 (m, 1H), 1.89(m, 1H), 1.74 (m, 2H), 1.48-1.28 (m, 6H), 0.87 (m, 3H).

Preparation N1 1-(3-Bromo-propyl)-3-chloro-benzene

[1347] Step A: Reduction

[1348] 3-(3-Chloro-phenyl)-propan-1-ol. A slurry of lithium aluminumhydride (2.08 g, 54.7 mmol) in THF (100 mL) was cooled to −78 C. Asolution of 3-chlorocinnamic acid (5.00 g, 27.4 mmol) in THF (25 mL) wasadded dropwise. The cold bath was removed and the mixture was warmed toroom temperature. After 6 h, the reaction was quenched by addition ofsodium sulfate decahydrate and the mixture was stirred overnight. Thesolids were removed by filtration with the aid of EtOAc and the organicsolution was washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to yield 3-(3-chloro-phenyl)-propan-1-ol (5.17 g)as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.07 (m, 4H), 5.06 (bs, 1H),3.67 (m, 2H), 2.69 (m, 2H), 1.89 (m, 2H).

[1349] Step B: Bromination

[1350] A solution of 3-(3-chloro-phenyl)-propan-1-ol (12.54 g, 73.6mmol) and N,N′-carbonyl diimidazole (13.12 g, 81 mmol) in CH₃CN wasstirred at room temperature for 1 h. Allyl bromide (53.43 g, 442 mmol)was added and the reaction was heated at reflux for 24 h. The reactionwas cooled to room temperature and brine and EtOAc were added. Theaqueous solution was extracted with EtOAc and the organic solution wasdried (MgSO₄), filtered, and concentrated. Flash chromatography providedthe title compound in about 85% yield. ¹H NMR (400 MHz, CDCl₃) δ7.30-7.09 (m, 4H), 3.38 (t, 2H), 2.76 (t, 2H), 2.15 (t, 2H).

Preparation O1 2-Indanyl-ethyl bromide

[1351] Step A: Reduction

[1352] 2-Indanylethanol. Lithium aluminum hydride (1 M in Et₂O, 14 mL,14 mmol) was slowly added to a solution of 2-indanylacetic acid (2.5 g,14 mmol) in Et₂O. The reaction mixture was heated at reflux for 2 h andwas cooled to room temperature. Water and EtOAc were added and theorganic solution was washed with water (2×) and brine (1×), dried overMgSO₄, filtered, and concentrated to afford 2-indanylethanol (2.1 g)which was used in the next step without further purification. ¹H NMR(400 MHz, CDCl₃) δ 7.08-7.24 (m, 4H), 3.75 (t, 2H), 3.07 (m, 2H), 2.61(m, 3H), 1.80 (m, 2H); MS 180 (M+18).

[1353] Step B: Bromination

[1354] 2-Indanyl-ethyl bromide. N,N-Carbonyl diimidazole (2.0 g, 12.3mmol) was added to a solution of 2-indanylethanol (2.0 g, 12.3 mmol) inacetonitrile. The reaction mixture was stirred at room temperature for 1h and allyl bromide (8.93 g, 73.8 mmol) was added. The reaction mixturewas heated to 70° C. for 24 h and was poured onto water. The aqueoussolution was extracted with Et₂O and the organic solution was washedwith water (1×) followed by brine (1×). The organic solution was driedover MgSO₄, filtered, and concentrated to afford the title compound(2.54 g). ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.25 (m, 4H), 3.48 (t, 2H),3.11 (m, 2H), 2.63 (m, 3H), 2.07 (m, 2H).

Preparation P1 Trans-3-[(3,5-Dichloro-phenyl)-allyl]-methanesulfonamide

[1355] A mixture of methanesulfonamide (3.27 g, 34.4 mmol),trans-(3,5-dichloro-phenyl)-allyl bromide (1.83 g, 6.88 mmol), K₂CO₃(0.95 g, 6.88 mmol) and CH₃CN was heated to 55° C. for 24 h. Thereaction mixture was poured onto EtOAc and 1N HCl. The organic solutionwas washed several times with 1 N HCl, dried over MgSO₄, filtered, andconcentrated. The product was purified by flash chromatography (30%EtOAc/hexanes to 40% EtOAc/hexanes) to afford the title compound (1.40g). ¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, 3H), 6.50 (d, 1H), 6.25 (m, 1H),4.45 (m, 1H), 3.94 (m, 2H), 3.00 (s, 3H).

Preparation Q1 (4-Methanesulfonylamino-phenyl)-butyric acid ethyl ester

[1356] Step A: Esterification

[1357] 4-(4-Amino-phenyl)-butyric acid ethyl ester. Catalytic sulfuricacid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g,33.48 mmol) in EtOH. The reaction mixture was stirred at roomtemperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixturewas heated at reflux for 24 h. The reaction mixture was concentrated invacuo and CH₂Cl₂ and water were added. The pH was adjusted to 7.0 withaqueous NaHCO₃ (satd). The organic solution was washed with water (1×)and brine (1×), dried over MgSO₄, filtered, and concentrated to afford4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). ¹H NMR (400 MHz,CDCl₃) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53(t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H).

[1358] Step B: Sulfonamide Formation

[1359] Pyridine (0.87 mL, 10.9 mmol) was added to a solution of4-(4-amino-phenyl)-butyric acid ethyl ester (1.50 g, 7.25 mmol) inCH₂Cl₂. The reaction mixture was cooled to 0° C. and methanesulfonylchloride (913 mg, 7.97 mmol) was added. The reaction was stirred at 0°C. for 1 h and at room temperature for 2 h. The mixture was poured intowater and CH₂Cl₂ was added. The pH was adjusted to 1.0 using 1N HCl. Theorganic solution was washed water (1×) and brine (1×), dried over MgSO₄,filtered, and concentrated in vacuo. The product crystallized onstanding to afford the title compound (2.03 g). ¹H NMR (400 MHz, CDCl₃)δ 7.09-7.32 (m, 4H), 4.12 (q, 2H), 2.97 (s, 3H), 2.60 (t, 2H), 2.30 (t,2H), 1.91 (m, 2H), 1.24 (t, 3H).

Preparation R1 [2-(2-Methanesulfonylamino-ethyl)-phenoxy]-acetic acidethyl ester

[1360] Step A: Sulfonamide Formation

[1361] N-[2-(2-Methoxy-phenyl)-ethyl]-methanesulfonamide. Pyridine (12.0mL, 150 mmol) was added to a solution of 2-methoxyphenethylamine (15.1g, 100 mmol) in CH₂Cl₂ (100 mL). The reaction was cooled to 0° C. andmethanesulfonyl chloride (12.6 g, 110 mmol) was added. The reaction wasstirred at 0° C. for 0.5 h and at room temperature for 2 h. Water wasadded and the aqueous layer was extracted with CH₂Cl₂ (2×). The organicsolution was washed water (1×) and brine (1×), dried over MgSO₄,filtered and concentrated to affordN-[2-(2-methoxy-phenyl)-ethyl]-methanesulfonamide (18.5 g).

[1362] Step B: Demethylation

[1363] N-[2-(2-Hydroxy-phenyl)-ethyl]-methanesulfonamide. Borontribromide (1.0 M in CH₂Cl₂, 80.8 mL, 80.8 mmol) was added to a solutionof N-[2-(2-methoxy-phenyl)-ethyl]-methanesulfonamide (18.5 g, 80.8 mmol)in CH₂Cl₂ (200 mL). The reaction was stirred at room temperature for 2 hand was poured onto water (200 mL). The aqueous layer was extracted withCH₂Cl₂ (2×) and the organic solution was washed with water (1×) andaqueous NaHCO₃ (satd, 1×). The organic solution was dried over MgSO₄,filtered, and concentrated to affordN-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide (16.8 g). ¹H NMR (400MHz, CDCl₃) δ 7.11 (m, 2H), 6.86 (m, 1H), 6.80 (m, 1H), 4.79 (m, 1H),3.39 (t, 2H), 2.88 (t, 2H), 2.77 (s, 3H).

[1364] Step C: Alkylation

[1365] A mixture of N-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide(4.3 g, 20 mmol), Nal (1.2 g, 8.0 mmol), K₂CO₃ (6.07 g, 44 mmol), ethylbromoacetate (3.34 g, 20 mmol), and DMF (70 mL) was stirred at roomtemperature for 24 h. The reaction was poured into water and the aqueoussolution was extracted with CH₂Cl₂. The organic solution was washed withwater (1×) followed by brine (1×). The organic solution was dried(MgSO₄), filtered, and concentrated. Flash chromatography (hexanes to7:3 hexanes:EtOAc) provided the title compound (800 mg). ¹H NMR (400MHz, CDCl₃) δ 7.18 (m, 2H), 6.93 (t, 1H), 6.71 (d, 1H), 4.97 (m, 1H),4.65 (s, 2H), 4.24 (q, 2H), 3.42 (m, 2H), 2.94 (t, 2H), 2.75 (s, 3H),1.27 (t, 3H); MS 319 (M+18).

Preparation S1 1-(3,5-Dichlorophenyl)-propyl bromide

[1366] Step A

[1367] 3-(3,5-Dichlorophenyl)-acrylic acid. A mixture of3,5-dichlorobenzaldehyde (15.0 g, 85.7 mmol), malonic acid (12.5 g,120.2 mmol), and piperidine (5 mL) was heated at 100° C. for 2 h and at150° C. for 1 h. The reaction was poured onto 3N HCl (200 mL) and theprecipitate was removed via filtration. The product was purified byrecrystallization (100 mL hot EtOH) to afford3-(3,5-dichlorophenyl)-acrylic acid (11.5 g). ¹H NMR (250 MHz, DMSO-d₆)δ 12.6 (bs, 1H), 7.83 (m, 2H), 7.64-7.51 (m, 2H), 6,72 (d, 1H).

[1368] Step B: Hydrogenation

[1369] 3-(3,5-Dichlorophenyl)-propionic acid. To a solution of 10% Pd/C(1.5 g) in THF (200 mL) was added 3-(3,5-dichlorophenyl)-acrylic acid(11.5 g). The reaction was hydrogenated on a Parr shaker at 50 psi for 3h. The catalyst was removed by filtration through celite and the organicsolution was concentrated in vacuo to afford3-(3,5-dichlorophenyl)-propionic acid (11.3 g). ¹H NMR (400 MHz, CDCl₃)δ 7.00-7.35 (m, 3H), 2.89 (t, 2H), 2.66 (t, 2H).

[1370] Step C: Reduction

[1371] 3-(3,5-Dichlorophenyl)-propanol. LiAlH₄ (1M in Et₂O, 10 mL, 10mmol) was slowly added to a solution of 3-(3,5-dichlorophenyl)-propionicacid (2.19 g, 10 mmol) in Et₂O (50 mL). The reaction was heated atreflux for 2 h. The reaction was cooled to room temperature and 2 N NaOH(1 mL) and aqueous NH₄Cl (satd., 3 mL) as carefully added. The solutionwas filtered through Celite and the filtrate was dried over MgSO₄,filtered, and concentrated. The product was purified by flashchromatography (25% EtOAc/hexanes) to afford3-(3,5-dichlorophenyl)-propanol (640 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.17(m, 1H), 7.07 (m, 2H), 3.64 (m, 2H), 2.65 (t, 2H), 1.84 (m, 2H).

[1372] Step D: Bromination

[1373] Triphenylphosphine (315 mg, 1.20 mmol) was added to a solution of3-(3,5-dichlorophenyl)-propanol (200 mg, 0.98 mmol) in CH₂Cl₂ (20 mL).The reaction mixture was cooled to 0° C. and bromine (207 mg, 1.30 mmol)was added dropwise. The reaction was stirred at 0° C. for 1 h and waswarmed to room temperature. The reaction was poured into water and theaqueous solution was extracted with CH₂Cl₂. The organic solution waswashed with brine, dried over MgSO₄, filtered, and concentrated invacuo. The product was purified by flash chromatography (hexanes) toafford the title compound (134 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (m,1H), 7.08 (m, 2H), 3.37 (t, 2H), 2.74 (t, 2H), 2.13 (m, 2H).

Preparation T1 4-(2-Methanesulfonylamino-ethoxy)-benzoic acid methylester

[1374] Step A: Deprotection

[1375] 4-(2-Amino-ethoxy)-benzoic acid methyl ester hydrochloride salt.To a solution of 4-[2-(2,2-dimethyl-propionylamino)-ethoxy]-benzoic acidmethyl ester (350 mg) in EtOH (6 mL) at 0° C. was added concentrated HCl(3 mL). The solution was warmed to room temperature and was concentratedin vacuo to provide the hydrochloride salt of 4-(2-amino-ethoxy)-benzoicacid methyl ester (266 mg) as a white solid which was used in the nextstep without further purification.

[1376] Step B: Sulfonamide Formation

[1377] Methanesulfonyl chloride (144 mg, 1.27 mmol) was added to asolution of 4-(2-amino-ethoxy)-benzoic acid methyl ester (266 mg, 1.15mmol) and pyridine (255 mg, 2.52 mmol) in CH₂Cl₂ (10 mL) at 0° C. Thesolution was warmed to room temperature and was stirred for 24 h. EtOAcwas added and the organic solution was washed with HCl (1N, 2×) followedby brine. The organic solution was dried (Na₂SO₄), filtered, andconcentrated to yield the title compound as a white solid (240 mg). ¹HNMR (400 MHz, CDCl₃) δ 7.99 (dd, 2H), 6.90 (dd, 2H), 4.77 (m, 1H), 4.15(t, 2H), 3.88 (s, 3H), 3.58 (m, 2H), 3.02 (s, 3H); MS 274 (M+1).

Preparation U1 7-(4-Butyl-phenylamino)-heptanoic acid methyl ester

[1378] Following the procedure described in Step A of Example 68,reductive amination of 4-butyl-benzaldehyde (1.50 g, 9.26 mmol) with7-aminoheptanoic methyl ester hydrochloride (1.51 g, 7.72 mmol) providedthe title compound (955 mg). ¹H NMR (300 MHz, CDCl₃) δ 7.29 (d, 2H),7.16 (d, 2H), 3.85 (s, 2H), 3.67 (s, 3H), 3.54 (m, 1H), 2.70 (t, 2H),2.59 (t, 2H), 2.29 (t, 2H), 1.60 (m, 6H), 1.32 (m, 6H), 0.92 (t, 3H); MS306 (M+1).

Preparation V1 [3-(Methanesulfonylamino-methyl)-phenoxy]-acetic acid

[1379] Step A: Sulfonamide Formation

[1380] N-(3-Methoxy-benzyl)-methanesulfonamide. Methanesulfonyl chloride(4.170 g, 36.4 mmol) was added to a solution of 3-methoxybenzylamine(5.000 g, 36.4 mmol) and triethylamine (3.946 g, 39.0 mmol) in THF (100mL) at room temperature. The mixture was stirred for 18 h and theinsolubles were removed by filtration. The organic solution wasconcentrated to a yellow oil which was purified by flash chromatography(6:4 hexanes:EtOAc to 1:1 hexanes:EtOAc) to yieldN-(3-methoxy-benzyl)-methanesulfonamide (7.431 g). ¹H NMR (400 MHz,CDCl₃) δ 7.26 (m, 1H), 6.92-6.82 (m, 3H), 4.62 (m, 1H), 4.28 (d, 2H),3.80 (s, 3H), 2.87 (s, 3H); MS 214 (M−1).

[1381] Step B: Demethylation

[1382] N-(3-Hydroxy-benzyl)-methanesulfonamide. A solution of BBr₃ (1.0M in CH₂Cl₂, 111 mL, 111 mmol) was slowly added to a solution ofN-(3-methoxy-benzyl)-methanesulfonamide (12.000 g, 55.7 mmol) inCH₂Cl₂(200 mL) at 0° C. The reaction was warmed to room temperature andwas stirred for 4 h. Methanol (100 mL) was cautiously added and thesolution was concentrated in vacuo. Flash chromatography (1:1hexanes:EtOAc) provided N-(3-hydroxy-benzyl)-methanesulfonamide (11.50g). ¹H NMR (400 MHz, CDCl₃) δ 7.20 (m, 1H), 6.84 (m, 2H), 6.77 (m, 1H),4.83 (bs, 1H), 4.24 (s, 2H), 2.86 (s, 3H); MS 201 (M+).

[1383] Step C: Alkylation

[1384] A mixture of N-(3-hydroxy-benzyl)-methanesulfonamide (6.000 g,29.82 mmol), methyl bromoacetate (4.562 g, 29.82 mmol), K₂CO₃ (4.121 g,29.82 mmol), and acetone (250 mL) was stirred at room temperature for 68h. The solids were removed by filtration and the solution wasconcentrated in vacuo. Purification by flash chromatography (1:1hexanes:EtOAc) provided the title compound (5.637 g). ¹H NMR (400 MHz,CDCl₃) δ 7.25 (m, 1H), 6.96 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 4.63(m, 3H), 4.28 (m, 2H), 3.80 (s, 3H), 2.86 (s, 3H); MS 274 (M+1).

[1385] It should be understood that the invention is not limited to theparticular embodiments described herein, but that various changes andmodifications may be made without departing from the spirit and scope ofthis novel concept as defined by the following claims.

Preparation W1 [3-(Methanesulfonylamino-methyl)-phenyl]-acetic acidethyl ester

[1386] Step A: Ester Formation

[1387] (3-Bromo-phenyl)-acetic acid ethyl ester. To a solution of3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH₃CN (150 mL) was addedK₂CO₃ (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol).The mixture was heated at reflux for 2.5 h and was cooled to roomtemperature. The volatiles were removed in vacuo and water was added.The aqueous solution was extracted with EtOAc (3×) and the combinedorganic extracts were washed with brine. The organic solution was dried(MgSO₄), filtered, and concentrated to provide (3-bromo-phenyl)-aceticacid ethyl ester (9.30 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (s,1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24(t, 3H).

[1388] Step B: Nitrile Formation

[1389] (3-Cyano-phenyl)-acetic acid ethyl ester. A mixture of(3-bromo-phenyl)-acetic acid ethyl ester (9.15 g, 37.6 mmol), coppercyanide (5.06 g, 56.5 mmol), and 1-methyl-2-pyrrolidinone (80 mL) wasplaced into an oil bath heated at 120° C. behind a protective shield.The reaction was heated to 200° C. for 1 h and additional copper cyanide(spatula tip) was added. After heating for an additional 0.5 h, thereaction was cooled to room temperature. The reaction was diluted withEtOAc and the organic solution was washed with water/ammonium hydroxidesolution (2:1 v/v) until the aqueous solution was no longer blue. Theorganic solution was washed with brine, dried (MgSO₄), filtered, andconcentrated. Flash chromatography (9:1 hexanes:EtOAc) provided(3-cyano-phenyl)-acetic acid ethyl ester (6.31 g) as a clear oil whichsolidified on standing. ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.50 (m, 3H),7.42 (m, 1H), 4.15 (q, 2H), 3.63 (s, 2H), 1.24 (t, 3H).

[1390] Step C: Nitrile Reduction

[1391] (3-Aminomethyl-phenyl)-acetic acid ethyl ester hydrochloride. Asolution of (3-cyano-phenyl)-acetic acid ethyl ester (6.3 g, 33.29 mmol)in EtOH (50 mL) was added to a mixture of 10% Pd/C (1.26 g) in EtOH (50mL) under Nitrogen. Additional EtOH (150 mL) was added followed by asolution of HCl in dioxane (4 M, 11.4 mL, 45.6 mmol). The mixture washydrogenated on a Parr shaker at 45 psi for 20 h and the catalyst wasremoved by filtration through celite. The solution was concentrated toafford (3-aminomethyl-phenyl)-acetic acid ethyl ester as thehydrochloride salt (7.31 g). ¹H NMR (400 MHz, CD₃OD) δ 7.42-7.32 (m,4H), 4.12 (q, 2H), 4.09 (s, 2H), 3.68 (s, 2H), 1.23 (t, 3H).

[1392] Step D: Sulfonamide Formation

[1393] [3-(Methanesulfonylamino-methyl)-phenyl]-acetic acid ethyl ester.

[1394] Methanesulfonyl chloride (2.6 mL, 34 mmol) was slowly added to asolution of (3-aminomethyl-phenyl)-acetic acid ethyl ester hydrochloride(7.31 g, 34 mmol) and triethylamine (9.8 mL, 70 mmol) in CH₂Cl₂ (100 mL)at 0° C. The mixture was stirred for 1 h and 1N aqueous HCl solution wasadded. The aqueous solution was extracted with CH₂Cl₂ (3×) and thecombined organic extracts were washed with brine. The organic solutionwas dried over MgSO₄, filtered, and concentrated. Purification by flashchromatography (1:1 hexanes:EtOAc) provided the title sulfonamide (8.56g) as a clear and colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.21 (m,4H), 4.70 (broad, 1H), 4.29 (d, 2H), 4.12 (q, 2H), 3.60 (s, 2H), 2.86(s, 3H), 1.24 (t, 3H).

ADDITIONAL GENERAL EXPERIMENTAL PROCEDURES

[1395] Medium pressure chromatography was performed on a Flash 40Biotage System (Biotage Inc., Dyax Corp., Charlottesville, Va.).

Examples 75-110

[1396] Examples 75-110 were prepared in an analogous manner to Example 1starting with the appropriate alkylating agents and sulfonamides in thealkylation Step A followed by ester hydrolysis in Step B with variationsin reaction temperature and time in Step A as noted.

Example 755-{3-[(6-Chloro-quinolin-2-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1397] Step A: Reaction time of 2 h at room temperature and 24 h at 75°C. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, 1H), 7.80 (d, 1H), 7.70 (s, 1H),7.52-7.54 (m, 2H), 7.35 (d, 1H), 6.50 (d, 1H), 4.54 (s, 2H), 4.02 (bs,1H), 3.19-3.24 (m, 2H), 2.89 (s, 2H), 2.62 (t, 2H), 1.72 (t, 2H); MS 453(M+14).

Example 765-(3-{[2-(3,5-Bis-trifluoromethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1398] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.69 (d, 1H), 7.48 (s, 1H), 7.25 (s, 2H), 6.84 (d, 1H),4.22 (t, 2H), 3.63 (t, 2H), 3.36 (t, 2H), 2.91-2.96 (m, 5H), 2.10 (t,2H); MS 519 (M+1).

Example 775-(3-{Methanesulfonyl-[2-(3-methoxy-phenoxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid

[1399] Step A: Reaction time of 30 min at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.70 (d, 1H), 7.15-7.19 (m, 1H), 6.84 (d, 1H), 6.51-6.54(m, 1H), 6.39-6.47 (m, 2H), 4.10 (t, 2H), 3.77 (s, 3H), 3.62 (t, 2H),3.35 (t, 2H), 2.91-2.97 (m, 5H), 2.07 (t, 2H); MS 412 (M−1).

Example 787-{[3-(3-Chloro-5-methoxy-phenoxy)-propyl]-methanesulfonyl-amino}-heptanoicacid

[1400] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 6.48-6.51 (m, 2H), 6.32 (s, 1H), 3.97 (t, 2H), 3.76 (s,3H), 3.33 (t, 2H), 3.16 (t, 2H), 2.82 (s, 3H), 2.33 (t, 2H), 2.07 (t,2H), 1.60-1.61 (m, 4H), 1.31-1.33 (m, 4H); MS 420 (M−1).

Example 795-(3-{[3-(3-Chloro-5-methoxy-phenoxy)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1401] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.69 (d, 1H), 6.81 (d, 1H), 6.47-6.50 (m, 2H), 6.30-6.31(m, 1H), 3.97 (t, 2H), 3.75 (s, 3H), 3.36 (t, 2H), 3.24 (t, 2H), 2.90(t, 2H), 2.83 (s, 2H), 1.98-2.11 (m, 4H); MS 460 (M−1).

Example 805-(3-{[3-(3,5-Dichloro-phenoxy)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1402] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.69 (d, 1H), 6.94 (t, 1H), 6.82 (d, 1H), 6.76 (s, 2H),3.99 (t, 2H), 3.35 (t, 2H), 3.24 (t, 2H), 2.90 (t, 2H), 2.84 (s, 3H),1.98-2.12 (m, 4H); MS 466 (M−1).

Example 815-(3-{[2-(3-Ethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1403] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.70 (d, 1H), 7.19 (t, 1H), 6.81-6.85 (m, 2H), 6.65-6.68(m, 2H), 4.11 (t, 2H), 3.64 (t, 2H), 3.36 (t, 2H), 2.91-2.95 (m, 2H),2.92 (s, 3H), 2.60 (q, 2H), 2.06-2.12 (m, 2H), 1.19-1.25 (m, 3H); MS 410(M⁺−1).

Example 825-(3-{[2-(3-Isopropyl-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1404] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.70 (d, 1H), 7.20 (t, 1H), 6.84-6.86 (m, 2H), 6.65-6.71(m, 2H), 4.11 (t, 2H), 3.64 (t, 2H), 3.37 (t, 2H), 2.92-2.95 (m, 2H),2.92 (s, 3H), 2.82-2.89 (m, 1H), 2.08 (t, 2H), 1.22 (d, 6H); MS 424(M⁺−1).

Example 835-(3-{Methanesulfonyl-[2-(3-trifluoromethyl-phenoxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid

[1405] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.68 (d, 1H), 7.37 (t, 1H), 7.21-7.23 (m, 1H), 7.05 (s,1H), 7.00 (d, 1H), 6.82 (d, 1H), 4.14 (t, 2H), 3.62 (t, 2H), 3.34 (t,2H), 2.92 (t, 2H), 2.90 (s, 3H), 2.07 (t, 2H); MS 450 (M⁺−1).

Example 842-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid

[1406] Step A: Reaction timeof 5 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ8.20 (s, 1H), 6.98 (s, 1H), 6.89 (s, 2H), 4.16 (t, 2H), 3.62 (t, 2H),3.37 (t, 2H), 3.08 (t, 2H), 2.93 (s, 3H), 2.15 (t, 2H); MS 452 (M⁺−1).

Example 855-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiophene-2-carboxylicacid

[1407] Step A: Reaction time of 5 h at 100° C. ¹H NMR (400 MHz, CDCl₃) δ7.57 (d, 1H), 7.22-7.26 (m, 2H), 7.12-7.18 (m, 3H), 6.86 (d, 1H),3.16-3.22 (m, 4H), 2.87 (t, 2H), 2.83 (s, 3H), 2.61 (t, 2H), 1.84-1.97(m, 4H); MS 380 (M⁺−1).

Example 867-{[3-(3,5-Dichloro-phenoxy)-propyl]-methanesulfonyl-amino}-heptanoicacid

[1408] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.70 (d, 1H), 7.19-7.23 (m, 1H), 6.84 (d, 1H), 6.61-6.70(m, 2H), 6.56 (d, 1H), 4.10 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H), 2.90(s, 3H), 2.86-2.95 (m, 2H), 2.07 (t, 2H); MS 401 (M⁺−1).

Example 875-(3-{Methanesulfonyl-[2-(3-fluoro-phenoxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid

[1409] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.70 (d, 1H), 7.19-7.23 (m, 1H), 6.84 (d, 1H), 6.61-6.70(m, 2H), 6.56 (d, 1H), 4.10 (t, 2H), 3.62 (t, 2H), 3.34 (t, 2H), 2.90(s, 3H), 2.86-2.95 (m, 2H), 2.07 (t, 2H); MS 400 (M⁺−1).

Example 885-(3-{Methanesulfonyl-[3-(3-methoxy-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid

[1410] Step A: Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.71 (d, 1H), 7.20 (t, 1H), 6.83 (d, 1H), 6.71-6.78 (m,3H), 3.78 (s, 3H), 3.17-3.22 (m, 4H), 2.89 (t, 2H), 2.81 (s, 3H), 2.61(t, 2H), 1.88-2.01 (m, 4H); MS 411 (M+).

Example 895-[3-(Benzofuran-2-ylmethyl-methanesulfonyl-amino)-propyl]-thiophene-2-carboxylicacid

[1411] Step A: Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.68 (d, 1H), 7.54 (d, 1H), 7.42 (d, 1H), 7.22-7.32 (m,2H), 6.82 (d, 1H), 6.68 (s, 1H), 4.58 (s, 2H), 3.32 (t, 2H), 2.92 (t,2H), 2.86 (s, 3H), 2.01-2.08 (m, 2H); MS 393 (M+).

Example 905-(3-{[2-(3-Chloro-5-methoxy-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1412] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.71 (d, 1H), 6.84 (d, 1H), 6.53 (s, 1H), 6.44 (s, 1H),6.28 (s, 1H), 4.08 (t, 2H), 3.75 (s, 3H), 3.60 (t, 2H), 3.34 (t, 2H),2.90-2.95 (m, 3H), 2.07 (t, 2H); MS 448 (M+).

Example 915-(3-{[2-(3-Ethoxy-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1413] Step A: Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.69 (d, 1H), 7.16 (t, 1H), 6.83 (d, 1H), 6.50-6.53 (m,1H), 6.39-6.44 (m, 1H), 4.10 (t, 2H), 3.98 (q, 2H), 3.62 (t, 2H), 3.35(t, 2H), 2.86-2.94 (m, 5H), 2.04-2.11 (m, 2H), 1.39 (t, 3H); MS 428(M+).

Example 92(4-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-butoxy)-aceticacid

[1414] Step A: Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 6.96 (s, 1H), 6.77 (s, 2H), 4.10 (s, 4H), 3.56-3.60 (m,4H), 3.30 (t, 2H), 2.89 (s, 3H), 1.73 -1.80 (m, 2H), 1.63-1.69 (m, 2H);MS 415 (M+1).

Example 93(3-{[(4-Butoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1415] Step A: Reaction time of 2 h at room temperature and 3 h at 70°C. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.33 (m, 1H), 7.17-7.25 (m, 5H), 6.85(d, 2H), 4.29 (s, 2H), 4.24 (s, 2H), 3.94 (t, 2H), 3.64 (s, 3H), 2.73(s, 3H), 1.72-1.79 (m, 2H), 1.44-1.53 (m, 2H), 0.97 (t, 3H); MS 423(M+18).

Example 94 7-[(4-Butoxy-benzyl)-methanesulfonyl-amino]-heptanoic acid

[1416] Step A: Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.23 (d, 2H), 6.85 (d, 2H), 4.29 (s, 2H), 3.94 (t, 2H),3.11 (t, 2H), 2.77 (s, 3H), 2.29 (t, 2H), 1.75 (m, 2H), 1.58-1.43 (m,6H), 1.24 (m, 4H), 0.96 (t, 3H); MS 403 (M+18).

Example 957-[(6-Chloro-quinolin-2-ylmethyl)-methanesulfonyl-amino]-heptanoic acid

[1417] Step A: Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 8.13 (d, 1H), 8.03 (d, 1H), 7.81 (s, 1H), 7.67 (m, 2H),4.72 (s, 2H), 3.26 (t, 2H), 2.99 (s, 3H), 2.25 (t, 2H), 1.52 (m, 4H),1.22 (m, 4H); MS 417 (M+18).

Example 96{3-[(Benzofuran-2-ylmethyl-methanesulfonyl-amino)-methyl]-phenyl}-aceticacid

[1418] Step A: Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.52-7.19 (m, 8H), 4.42 (s, 2H), 4.37 (s, 2H), 3.63 (s,2H), 2.91 (s, 3H).

Example 97(3-{[(4-Ethyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid

[1419] Step A:(3-{[(4-Ethyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acidmethyl ester. Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.29-7.33 (m, 1H), 7.16-7.25 (m, 7H), 4.30 (d, 4H), 3.69(s, 3H), 3.62 (s, 2H), 2.76 (s, 3H), 2.64 (q, 2H), 1.54 (t, 3H); MS 376(M⁺+1).

[1420] Step B:(3-{[(4-Ethyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.34 (m, 1H), 7.15-7.25 (m, 7H),4.29 (d, 4H), 3.65 (s, 2H), 2.75 (s, 3H), 2.63 (q, 2H), 1.20-1.24 (m,3H).

Example 98(3-{[Methanesulfonyl-(4-propyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1421] Step A:(3-{[Methanesulfonyl-(4-propyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. Reaction time of 24 h at room temperature. MS 408(M⁺+18).

[1422] Step B:(3-{[Methanesulfonyl-(4-propyl-benzyl)-amino]-methyl}-phenyl)-aceticacid MS 374 (M⁺−1).

Example 99(3-{[(4-Benzyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1423] Step A:(3-{[(4-Benzyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. Reaction time on 24 h at room temperature. ¹H NMR(400 MHz, CDCl₃) δ 7.14-7.29 (m, 13H), 4.28 (d, 4H), 3.95 (s, 2H), 3.67(s, 3H), 3.59 (s, 2H), 2.75 (s, 3H); MS 456 (M⁺+18).

[1424] Step B:(3-{[(4-Benzyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.29 (m, 13H), 4.27 (d, 4H), 3.94(s, 2H), 3.61 (s, 2H), 3.73 (s, 3H); MS 422 (M⁺−1).

Example 100(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid

[1425] Step A:(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 4.30 (d, 4H), 3.69 (s, 3H),3.61 (s, 2H), 2.82-2.86 (m, 2H), 2.59 (t, 2H), 1.78-1.84 (m, 2H), 1.58(t, 2H).

[1426] Step B:(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.32 (m, 8H), 4.30 (d, 4H), 3.64(s, 2H), 2.81-2.90 (m, 2H), 2.59 (t, 2H), 1.74-1.83 (m, 2H), 1.54-1.61(m, 2H), 1.31-1.40 (m, 2H), 0.87-0.97 (m, 6H); MS 416 (M⁺−1).

Example 1017-{Methanesulfonyl-[3-(5-methyl-thiophen-2-yl)-propyl]-amino}-heptanoicacid

[1427] Step A:7-{Methanesulfonyl-[3-(5-methyl-thiophen-2-yl)-propyl]-amino}-heptanoicacid methyl ester. Reaction time of 1 h at 60° C. ¹H NMR (400 MHz,CDCl₃) δ 6.55 (d, 2H), 3.66 (s, 2H), 3.12-3.21 (m, 4H), 2.80 (s, 3H),2.76-2.80 (m, 2H), 2.42 (s, 3H), 2.30 (t, 2H), 1.89-1.97 (m, 2H),1.53-1.65 (m, 4H), 1.31-1.36 (m, 4H); MS 376 (M⁺+1), 393 (M⁺+18).

[1428] Step B:7-{Methanesulfonyl-[3-(5-methyl-thiophen-2-yl)-propyl]-amino}-heptanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.53-6.57 (m, 2H), 3.12-3.21 (m, 4H),2.80 (s, 3H), 2.78 (t, 2H), 2.42 (s, 3H), 2.34 (t, 2H), 1.89-1.97 (m,2H), 1.54-1.66 (m, 4H), 1.30-1.40 (m, 4H); MS 379 (M⁺+18).

Example 1025-{3-[(3-Furan-2-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1429] Step A:5-{3-[(3-Furan-2-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.62 (d, 1H), 7.29 (d, 1H), 6.80 (d, 1H), 6.26-6.28 (m,1H), 6.00 (d, 1H), 3.85 (s, 3H), 3.18-3.23 (m, 4H), 2.88 (t, 2H), 2.81(s, 3H), 2.66 (t, 2H), 1.90-2.03 (m, 4H).

[1430] Step B:5-{3-[(3-Furan-2-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, 1H), 7.29 (d, 1H), 6.84 (d,1H), 6.26-6.28 (m, 1H), 6.00-6.01 (m, 1H), 3.22 (q, 4H), 2.90 (t, 2H),2.82 (s, 3H), 2.67 (t, 2H), 1.88-2.03 (m, 4H); MS 370 (M⁺−1).

Example 1037-{Methanesulfonyl-[3-(3-methoxyphenyl)-propyl]-amino}-heptanoic acid

[1431] Step A:7-{Methanesulfonyl-[3-(3-methoxyphenyl)-propyl]-amino}-heptanoic acidmethyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400 MHz,CDCl₃) δ 7.18-7.22 (m, 1H), 6.75-6.78 (m, 2H), 6.73 (s, 1H), 3.79 (s,3H), 3.66 (s, 3H), 3.11-3.20 (m, 4H), 2.80 (s, 3H), 2.61 (t, 2H), 2.29(t, 2H), 1.88-1.95 (m, 2H), 1.52-1.64 (m, 4H), 1.28-1.32 (m, 4H).

[1432] Step B:7-{Methanesulfonyl-[3-(3-methoxyphenyl)-propyl]-amino}-heptanoic acid.¹H NMR (400 MHz, CDCl₃) δ 7.18-7.22 (m, 1H), 6.75-6.78 (m, 2H), 6.73 (s,1H), 3.79 (s, 3H), 3.11-3.20 (m, 4H), 2.80 (s, 3H), 2.61 (t, 2H), 2.34(t, 2H), 1.89-1.95 (m, 2H), 1.53-1.66 (m, 4H), 1.29-1.36 (m, 4H).

Example 104[3-({[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1433] Step A:[3-({[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid ethyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.17-7.31 (m, 8H), 5.70 (t, 1H), 4.31 (s, 4H), 4.12-4.17(m, 4H), 3.60 (s, 2H), 2.76 (s, 3H), 2.06 (s, 3H), 1.83-1.88 (m, 1H),1.57-1.75 (m, 1H), 1.20-1.27 (m, 9H), 0.85 (t, 3H); MS 525 (M⁺+18).

[1434] Step B:[3-({[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.28 (m, 7H), 7.02 (s, 1H), 4.61(t, 1H), 4.29 (d, 4H), 3.53 (s, 2H), 2.79 (s, 3H), 1.60-1.77 (m, 2H),1.18-1.36 (m, 6H), 0.83 (t, 3H); MS 432 (M⁺−1).

Example 1055-(3-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1435] Step A:5-(3-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. Reaction time of 18 h at 60° C. ¹H NMR (400 MHz,CDCl₃) δ 7.60-7.62 (m, 1H), 7.15-7.20 (m, 1H), 6.93-6.95 (m, 1H),6.79-6.80 (m, 2H), 6.71-6.73 (m, 1H), 4.09 (t, 2H), 3.84 (s, 3H), 3.60(t, 2H), 3.32 (t, 2H), 2.89 (s, 3H), 2.86-2.94 (m, 2H), 2.01-2.08 (m,2H).

[1436] Step B:5-(3-{[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, 1H), 7.11-7.22 (m, 1H),6.91-6.93 (m, 1H), 6.81 (s, 2H), 6.69-6.72 (m, 1H), 4.07 (t, 2H), 3.59(t, 2H), 3.31 (t, 2H), 2.88 (s, 3H), 2.78-2.91 (m, 2H), 2.01-2.05 (m,2H).

Example 1062-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiazole-4carboxylic acid

[1437] Step A:2-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiazole-4carboxylic acid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400MHz, CDCl₃) δ 8.03 (s, 1H), 7.23-7.27 (m, 2H), 7.13-7.18 (m, 3H), 4.38(q, 2H), 3.18-3.25 (m, 4H), 3.06 (t, 2H), 2.79 (s, 3H), 2.61 (t, 2H),2.05-2.13 (m, 2H), 1.86-1.94 (m, 2H), 1.37 (t, 3H); MS 411 (M⁺+1).

[1438] Step B:2-{3-[Methanesulfonyl-(3-phenyl-propyl)-amino]-propyl}-thiazole-4carboxylic acid. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.10-7.24 (m,5H), 3.17-3.28 (m, 4H), 3.04 (t, 2H), 2.83 (s, 3H), 2.61 (t, 2H),2.02-2.09 (m, 2H), 1.85-1.92 (m, 2H); MS 381 (M⁺−1).

Example 1072-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid

[1439] Step A:2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400 MHz,CDCl₃) δ 8.06 (s, 1H), 7.16-7.23 (m, 3H), 7.05 (d, 1H), 4.40 (q, 2H),3.09 (t, 2H), 3.19-3.28 (m, 4H), 2.83 (s, 3H), 2.62 (t, 2H), 2.08-2.17(m, 2H), 1.87-1.95 (m, 2H), 1.39 (t, 3H); MS 445 (MH⁺).

[1440] Step B:2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.21-7.25 (m, 2H),7.12-7.16 (m, 2H), 3.20-3.30 (m, 4H), 3.07 (t, 2H), 2.86 (s, 3H), 2.63(t, 2H), 2.05-2.12 (m, 2H), 1.86-1.94 (m, 2H); MS 415 (M⁺−1).

Example 1082-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid

[1441] Step A:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400 MHz,CDCl₃) δ 8.00 (s, 1H), 7.21 (d, 2H), 7.11 (d, 2H), 4.38 (q, 2H), 4.33(s, 2H), 3.23 (t, 2H), 2.96 (t, 2H), 2.78 (s, 3H), 2.56 (t, 2H),1.96-2.03 (m, 2H), 1.50-1.58 (m, 2H), 1.37 (t, 3H), 1.26-1.33 (m, 2H),0.89 (t, 3H); MS 439 (M+1).

[1442] Step B:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.25 (d, 2H), 7.12 (d,2H), 4.32 (s, 2H), 3.22-3.28 (m, 2H), 2.88-2.91 (m, 2H), 2.88 (s, 3H),2.57 (t, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.27-1.32 (m, 2H), 0.90 (t,3H); MS 409 (M−1).

Example 109(5-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid

[1443] Step A:(5-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid methyl ester. Reaction time of 24 h at room temperature.

[1444] Step B:(5-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.32 (m, 6H), 4.40 (s, 2H), 3.80(s, 2H), 2.75 (s, 3H), 1.80 (m, 2H), 0.85 (d, 6H); MS 394 (M−1).

Example 1102-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid

[1445] Step A:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid ethyl ester. Reaction time of 5 h at 100° C. ¹H NMR (400 MHz,CDCl₃) δ 8.00 (s, 1H), 7.21 (d, 2H), 7.11 (d, 2H), 4.38 (q, 2H), 4.33(s, 2H), 3.23 (t, 2H), 2.96 (t, 2H), 2.78 (s, 3H), 2.56 (t, 2H),1.96-2.03 (m, 2H), 1.50-1.58 (m, 2H), 1.37 (t, 3H), 1.26-1.33 (m, 2H),0.89 (t, 3H); MS 439 (M⁺+1).

[1446] Step B:2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiazole-4-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.25 (d, 2H), 7.12 (d,2H), 4.32 (s, 2H), 3.22-3.28 (m, 2H), 2.88-2.91 (m, 2H), 2.88 (s, 3H),2.57 (t, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.27-1.32 (m, 2H), 0.90 (t,3H); MS 409 (M⁺−1).

Example 1117-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

[1447] Step A: 2-[2-(3,5-Dichloro-phenoxy)-ethyl]-isoindole-1,3-dione. Asolution of 1-(2-bromo-ethoxy)-3,5-dichloro-benzene (2.41 g, 8.93 mmol)and potassium phthalimide (2.00 g, 10.64 mmol) in DMF (7.6 mL) washeated at 85° C. for 1 h. The reaction was cooled to room temperatureand chloroform was added. The organic solution was washed with 0.2 Naqueous NaOH followed by water. The organic solution was dried (Na₂SO₄),filtered, and concentrated. The residue was suspended in Et₂O and thesolid was collected by filtration to provide the title compound (2.21g). ¹HNMR (400 MHz, CDCl₃) δ 7.82 (m, 2H), 7.77 (m, 2H), 6.89 (m, 1H),6.88 (m, 2H), 4.16 (t, 2H), 4.05 (t, 2H); MS 336 (M+).

[1448] Step B: 2-(3,5-Dichloro-phenoxy)-ethylamine. A solution of2-[2-(3,5-dichloro-phenoxy)-ethyl]-isoindole-1,3-dione (1.29 g, 3.84mmol) and hydrazine hydrate (202 mg, 4.05 mmol) in MeOH (16 mL) washeated at reflux for 2 h. The mixture was cooled to room temperature andEt₂O was added. The suspension was shaken with 40% aqueous potassiumhydroxide. The aqueous solution was extracted with Et₂O (3×) and thecombined organic layers were dried (K₂CO₃), filtered, and concentratedto provide the title compound (870 mg). ¹HNMR (400 MHz, CDCl₃) δ 6.95(m, 1H), 6.80 (m, 2H), 3.95 (m, 2H), 3.07 (t, 2H), 1.70 (bs, 2H).

[1449] Step C: N-[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonamide.The title compound was prepared from2-(3,5-Dichloro-phenoxy)-ethylamine, Et₃N, and methanesulfonyl chlorideusing the procedure described in Step 2 of Preparation A1.Recrystallization from EtOH provided the title compound. ¹HNMR (400 MHz,CDCl₃) δ 6.93 (m, 1H), 6.74 (m, 2H), 5.09 (m, 1H), 4.01 (t, 2H), 3.47(q, 2H), 2.96 (s, 3H).

[1450] Step D:7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid ethyl ester. A solution of NaH (60% in oil, 338 mg, 8.45 mmol) inDMF (23 mL) was cooled to 0° C. followed by addition ofN-[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonamide (2.0 g, 7.04mmol). The reaction was stirred at room temperature for 0.5 h and wascooled to 0° C. followed by addition of ethyl 7-bromoheptanoate (2.0 g,8.45 mmol). The reaction was heated at 65° C. for 3 h and was cooled toroom temperature. EtOAc was added and the organic solution was washedconsecutively with 1N HCl, water, and brine. The organic solution wasdried (MgSO₄), filtered, and concentrated. Purification by flashchromatography (4:1 hexanes:EtOAc) provided the title compound (2.84 g).¹HNMR (400 MHz, CDCl₃) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.06 (m, 5H), 3.56(t, 2H), 3.22 (t, 2H), 2.86 (s, 3H), 2.26 (t, 2H), 1.60 (m, 4H), 1.32(m, 4H), 1.22 (t, 3H).

[1451] Step E:7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid. The title compound was prepared from7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid ethyl ester using the procedure described in Step B of Example 1with 2N NaOH. Purification by flash chromatography (1% MeOH in CH₂Cl₂)provided the title acid. ¹HNMR (400 MHz, CDCl₃) δ 6.95 (m, 1H), 6.75 (m,2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t,2H), 1.61 (m, 4H), 1.33 (m, 4H); MS 411 (M−1).

[1452] Example numbers 112-122 are not used in this specification

Examples 123-137

[1453] Examples 123-137 were prepared in an analogous manner to Example1 starting with the appropriate alkylating agents and sulfonamides inthe alkylation Step A followed by ester hydrolysis in Step B withvariations in reaction temperature and time in Step A as noted.

Example 123[5-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid

[1454] Step A:[5-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid methyl ester. Reaction time of 24 h at room temperature.

[1455] Step B:[5-({[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.06-7.36 (M, 4H), 6.86 (m, 2H), 4.40(s, 2H), 3.80 (s, 2H), 2.90 (s, 3H), 3.00 (t, 2H, J=7.0), 2.40 (t, 2H,J=7.0), 1.70 (m, 2H); MS 399 (M−1).

Example 124[5-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid

[1456] Step A:[5-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid methyl ester. Reaction time of 24 h at room temperature.

[1457] Step B:[5-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-thiophen-2-yl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.60 (m, 5H), 4.60 (s, 2H), 4.10(m, 2H), 3.80 (s, 2H), 3.60 (m, 2H), 2.90 (s, 3H); MS 436 (M−1), 438(M+1).

Example 125(5-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid

[1458] Step A:(5-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid methyl ester. Reaction time of 24 h at room temperature.

[1459] Step B:(5-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-thiophen-2-yl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-7.30 (m, 4H), 6.80 (d, 1H, J=4.0),6.70 (d, 1H, J=4.0), 4.40 (s, 2H), 4.30 (s, 2H), 3.80 (s, 2H), 2.90 (s,3H), 2.60 (m, 2H), 1.60 (m, 2H), 1.30 (m, 2H), 0.90 (t, 3H, J=7.0); MS394 (M−1).

Example 1265-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

[1460] Step A:5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. Reaction time of 72 h at room temperature; MS 450(M+1).

[1461] Step B:5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.70 (m, 5H), 6.19 (d, 1H, J=3.8),4.20 (t, 2H, J=7.0), 3.80 (m, 2H), 3.25-3.40 (m, 4H), 2.95 (s, 3H), 2.65(m, 2H), 1.80-2.00 (m, 2H); MS 435 (M−1), 436 (M+1).

Example 127Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

[1462] Step A:Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. Reaction time of 72 h at room temperature; MS 446(M+).

[1463] Step B:Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-7.50 (m, 4H), 6.00-6.60 (m, 3H),4.00 (d, 2H, J=5.0), 3.20 (m, 2H), 2.60-2.70 (m, 2H), 1.70-2.00 (m, 2H);MS 430 (M−1), 432 (M+1).

Example 1283-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-benzoicacid

[1464] Step A:3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-benzoicacid methyl ester. Reaction time of 2 h at room temperature; MS 446(M+).

[1465] Step B:3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-benzoicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.90 (m, 7H), 4.20 (t, 2H, J=6.7),3.20-3.30 (m, 4H), 2.85 (s, 3H), 2.30 (t, 2H, J=6.8); MS 431 (M−1).

Example 129[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-phenyl]-aceticacid

[1466] Step A:[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-phenyl]-aceticacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.03-7.29 (m, 8H), 3.68 (s, 3H), 3.59 (s, 2H), 3.15-3.20(m, 4H), 2.80 (s, 3H), 2.58-2.64 (m, 4H), 1.84-1.94 (m, 4H).

[1467] Step B:[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.02-7.29 (m, 8H), 3.61 (s, 2H),3.14-3.19 (m, 4H), 2.78 (s, 3H), 2.57-2.80 (m, 4H), 1.82-1.93 (m, 4H).

Example 1305-{3-[(3-Benzo[1,3]dioxol-5-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1468] Step A:5-{3-[(3-Benzo[1,3]dioxol-5-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.61 (d, 1H), 6.79 (d, 1H), 6.58-6.72 (m, 3H), 5.91 (s,2H), 3.85 (s, 3H), 3.14-3.21 (m, 4H), 2.87 (t, 2H), 2.80 (s, 3H), 2.55(t, 2H), 1.82-1.99 (m, 4H).

[1469] Step B:5-{3-[(3-Benzo[1,3]dioxol-5-yl-propyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H), 6.83 (d, 1H), 6.59-6.73(m, 3H), 5.91 (s, 2H), 3.15-3.22 (m, 4H), 2.89 (t, 2H), 2.81 (s, 3H),2.55 (t, 2H), 1.83-2.01 (m, 4H); MS 424 (M−1).

Example 131(3-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1470] Step A:(3-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. Reaction time of 2 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.20-7.32 (m, 6H), 7.11 (d, 2H), 4.30 (d, 4H), 3.69 (s,3H), 3.62 (s, 3H), 3.62 (s, 3H), 2.75 (s, 3H), 2.46 (s, 2H), 1.81-1.88(m, 1H), 0.88 (d, 6H); MS 404 (M+1), 426 (M+23).

[1471] Step B:(3-{[(4-Isobutyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.31 (m, 6H), 7.10 (d, 2H), 4.29(d, 4H), 3.63 (s, 2H), 2.73 (s, 3H), 2.45 (d, 2H), 1.80-1.87 (m, 1H),0.88 (d, 6H).

Example 132 7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoicacid

[1472] Step A: 7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoicacid ethyl ester. Reaction time of 24 h at room temperature. ¹H NMR (400MHz, CDCl₃) δ 7.20-7.30 (m, 4H), 4.35 (s, 2H), 4.10 (q, 2H), 3.15 (t,2H), 2.85-2.95 (m, 1H), 2.80 (s, 3H), 2.25 (t, 2H), 1.48-1.62 (m, 4H),1.18-1.32 (m, 13H); MS 384 (M+1).

[1473] Step B: 7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoicacid. MS 356 (M+1).

Example 1337-{[2-(3,5-Difluoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

[1474] Step A:7-{[2-(3,5-Difluoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid methyl ester. Reaction time of 24 h at 50° C. ¹H NMR (400 MHz,CDCl₃) δ 6.39-6.45 (m, 3H), 4.08 (t, 2H), 3.65 (s, 2H), 3.58 (t, 2H),3.23-3.27 (m, 2H), 2.88 (s, 3H), 2.30 (t, 2H), 1.57-1.65 (m, 5H),1.33-1.35 (m, 4H); MS 394 (M+1).

[1475] Step B:7-{[2-(3,5-Difluoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.39-6.45 (m, 3H), 4.08 (t, 2H), 3.58(t, 2H), 3.25 (t, 2H), 2.35 (t, 2H), 1.64 (m, 5H), 1.24-1.37 (m, 4H); MS380 (M−1).

Example 1347-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid

[1476] Step A:7-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid methyl ester. Reaction time of 24 h at 50° C. ¹H NMR (400 MHz,CDCl₃) δ 6.61 (s, 1H), 6.49 (s, 2H), 4.06-4.14 (m, 2H), 3.65 (s, 3H),3.61 (t, 2H), 3.26 (t, 2H), 2.90 (s, 3H), 2.27-2.33 (m, 8H), 1.55-1.63(m, 4H), 1.25 (bs, 4H); MS 385 (M+1).

[1477] Step B:7-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.61 (s, 1H), 6.49 (s, 2H), 4.06-4.07(m, 2H), 3.59-3.61 (m, 2H), 3.27 (t, 2H), 2.91 (s, 3H), 2.34 (t, 2H),2.27 (s, 6H), 1.63-1.65 (m, 4H), 1.36 (bs, 4H); MS 370 (M−1).

Example 135(2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-phenyl)-aceticacid

[1478] Step A:(2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.11-7.23 (m, 7H),6.99-7.01 (m, 1H), 4.31 (s, 2H), 3.63 (s, 3H), 3.54 (s, 2H), 3.19 (t,2H), 2.78 (s, 3H), 2.49-2.59 (m, 4H), 1.72-1.80 (m, 2H), 1.54-1.59 (m,2H), 1.27-1.36 (m, 2H), 0.89 (t, 3H); MS 432 (M+1).

[1479] Step B:(2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.27 (m, 7H), 7.02 (d, 1H), 4.32(s, 2H), 3.59 (s, 2H), 3.21 (t, 2H), 2.79 (s, 3H), 2.50-2.61 (m, 4H),1.73-1.81 (m, 2H), 1.54-1.62 (m, 2H), 1.29-1.38 (m, 2H), 0.92 (t, 3H);MS 416 (M−1).

Example 1365-(3-{[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1480] Step A:5-(3-{[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. Reaction time of 24 h at room temperature. ¹H NMR(400 MHz, CDCl₃) δ 7.61 (d, 1H), 6.80 (d, 1H), 6.67-6.70 (m, 1H), 6.41(d, 1H), 6.24-6.27 (m, 1H), 5.91 (s, 2H), 4.03 (t, 2H), 3.85 (s, 3H),3.59 (t, 2H), 3.33 (t, 2H), 2.89 (s, 3H), 2.88-2.92 (m, 2H), 2.01-2.08(m, 2H); MS 442 (M+1).

[1481] Step B:5-(3-{[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, 1H), 6.84 (d, 1H), 6.68 (d,1H), 6.40 (s, 1H), 6.24-6.27 (m, 1H), 5.91 (s, 2H), 4.03 (t, 2H), 3.60(t, 2H), 3.34 (t, 2H), 2.90 (s, 3H), 2.90-2.94 (m, 2H), 2.02-2.10 (m,2H); MS 426 (M−1).

Example 137[3-({[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1482] Step A:[3-({[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.33 (m, 5H),6.93-6.95 (m, 1H), 6.80-6.81 (m, 1H), 6.69-6.71 (m, 1H), 4.49 (s, 2H),3.96-4.02 (m, 2H), 3.67 (s, 2H), 3.54-3.67 (m, 4H), 2.94 (s, 3H).

[1483] Step B:[3-({[2-(3-Chloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.33 (m, 5H), 6.91 (d, 1H), 6.78(s, 1H), 6.66-6.69 (m, 1H), 4.48 (s, 2H), 3.98 (t, 2H), 3.62 (s, 2H),3.56 (t, 2H), 2.92 (s, 3H).

Example 138[3-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid

[1484] Step A: Alkylation

[1485][3-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid tert-butyl ester. Step A was performed with the appropriatestarting materials in an analagous manner to Step A of Example 1 with areaction time of 24 h at room temperature; MS 466 (M+).

[1486] Step B: Ester Hydrolysis

[1487][3-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid. A solution of[3-(2-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid tert-butyl ester (170 mg, 0.36 mmol) in HCl/dioxane (5 mL) wasstirred for 48 h at room temperature. The reaction was concentrated andthe residue was taken up in dilute aqueous NaOH (10 mL, pH=9.3). Theaqueous solution was washed with EtOAc (10 mL) and the layers wereseparated. The aqueous layer after extraction with EtOAc (10 mL) wasacidified with dilute aqueous HCl to a pH of 2.5. After extraction ofthe acidic aqueous layer with EtOAc (10 mL) the organic solution wasdried over MgSO₄, filtered, and concentrated to afford the titlecompound as an oil (20 mg). ¹H NMR (400 MHz, CDCl₃) δ 6.90-7.50 (m, 8H),3.00-3.30 (m, 4H), 2.95 (s, 3H), 2.45-2.85 (m, 4H), 1.80 (m, 2H); MS 408(M−1).

Examples 139-140

[1488] Examples 139-140 were prepared in an analogous manner to Example138 starting with the appropriate alkylating agents and sulfonamides inthe alkylation Step A followed by ester hydrolysis in Step B withvariations in reaction temperature and time in Step A as noted.

Example 139[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid

[1489] Step A:[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid tert-butyl ester. Reaction time of 4 h at room temperature.

[1490] Step B:[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.70-7.50 (m, 7H), 4.20 (m, 2H), 3.25(m, 4H), 2.95 (s, 3H), 2.35-2.65 (m, 2H); MS 445 (M−1).

Example 1405-(3-{[3-(3-Chloro-phenyl)-propyl]-trifluoroacetyl-amino}-propyl)-thiophene-2-carboxylicacid

[1491] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-trifluoroacetyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. Reaction time of 24 h at room temperature. MS 508(M+18).

[1492] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-trifluoroacetyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.80 (m, 6H), 3.22 (m, 4H), 2.80(m, 2H), 2.63 (m, 2H), 1.60-2.02 (m, 4H); MS 433 (M−1).

Example 141(3-{[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1493] Step A: Reductive Amination

[1494](3-{[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl-amino]-methyl}-phenyl)-aceticacid ethyl ester. To a solution of 1,4-benzodioxan-6-carboxyaldehyde(100 mg, 0.609 mmol) and (3-aminomethyl-phenyl)-acetic acid ethyl esterhydrochloride (148 mg, 0.645 mmol) in MeOH (2.5 mL) was addedtriethylamine (65 mg, 0.646 mmol). The reaction was stirred for 3 h, wascooled to 0° C., and NaBH₄ (37 mg, 0.975 mmol) was added. After stirringat room temperature for 10 minutes, a 1:1 mixture of saturated aqueousNaHCO₃:H₂O was added. The product was extracted into CH₂Cl₂ and theorganic solution was washed with water followed by brine. The organicsolution was dried over MgSO₄, filtered, and concentrated to yield thetitle compound (202 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.14-7.27 (m, 4H),6.84 (s, 1H), 6.78 (s, 2H), 4.22 (s, 4H), 4.12 (q, 2H), 3.75 (s, 2H),3.67 (s, 2H), 3.57 (s, 2H), MS 343 (M+1).

[1495] Step B: Sulfonamide Formation

[1496](3-{[(2,3-Dihydro-benzo[1,4dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid ethyl ester. To a solution of(3-{[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl-amino]-methyl}-phenyl)-aceticacid ethyl ester (200 mg, 0.585 mmol) and triethylamine (71 mg, 0.702mmol) in CH₂Cl₂ (10 mL) was added methanesulfonyl chloride (0.05 mL,0.643 mmol). The reaction was stirred for 16 h and was diluted withCH₂Cl₂. The organic solution was washed with water followed by brine,dried over MgSO₄, filtered, and concentrated. The product was purifiedby flash chromatography (20% EtOAc in hexanes to 40% EtOAc in hexanes)to provide the title compound (210 mg). ¹H NMR (400 MHz, CDCl₃) δ7.20-7.31 (m, 4H), 6.75-6.82 (m, 3H), 4.30 (s, 2H), 4.24 (s, 4H), 4.20(s, 2H), 4.13 (q, 2H), 3.59 (s, 2H), 2.74 (s, 3H), 1.24 (t, 3H); MS 420(M+), 437 (M+17).

[1497] Step C: Ester Hydrolysis

[1498](3-{[(2,3-Dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. To a solution of(3-{[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid ethyl ester (210 mg, 0.5 mmol) in MeOH (3 mL) at 0° C. was addedaqueous NaOH (2N, 0.5 mL). The reaction was stirred at room temperaturefor 16 h and was diluted with 1N HCl. The product was extracted intoCH₂Cl₂ and the organic solution was washed with water followed by brine.The organic solution was dried over MgSO₄, filtered, and concentrated toprovide the title compound (165 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.32(m, 4H), 6.73-6.81 (m, 3H), 4.29 (s, 2H), 4.22 (s, 4H), 4.18 (s, 2H),3.63 (s, 2H), 2.75 (s, 3H).

Examples 142-162

[1499] Examples 142-162 were prepared in an analogous manner to Example141 starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired sulfonamide in Step B and esterhydrolysis in Step C.

Example 142(3-{[(5-Ethyl-thiophen-2-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1500] Step A:(3-{[(5-Ethyl-thiophen-2-ylmethyl)-amino]-methyl}-phenyl)-acetic acidethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.29 (m, 4H), 6.70 (d, 1H),6.59 (d, 1H), 4.11-4.15 (m, 2H), 3.90 (s, 2H), 3.80 (s, 2H), 3.58 (s,2H), 2.76-2.82 (m, 2H), 1.84 (bs, 1H), 1.20-1.29 (m, 6H); MS 318 (M⁺+1).

[1501] Step B:(3-{[(5-Ethyl-thiophen-2-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.35 (m, 4H), 6.77 (d,1H), 6.63-6.64 (m, 1H), 4.40 (s, 2H), 4.38 (s, 2H), 4.15 (q, 2H), 3.62(s, 2H), 2.82 (q, 2H), 2.77 (s, 3H), 1.23-1.31 (m, 6H); MS 413 (M⁺+18).

[1502] Step C:(3-{[(5-Ethyl-thiophen-2-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.33 (m, 2H), 6.74 (s, 1H), 6.61(s, 1H), 4.38 (s, 2H), 4.36 (s, 2H), 3.66 (s, 2H), 2.80 (q, 2H), 2.75(s, 3H), 1.25-1.30 (m, 3H); MS 366 (M⁺−1).

Example 143(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-aceticacid

[1503] Step A:(3-{[(5-Phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, 2H), 7.34 (t, 2H),7.14-7.29 (m, 5H), 6.55 (d, 1H), 6.24 (d, 1H), 3.81 (d, 4H), 3.66 (s,3H), 3.59 (s, 2H), 1.73 (bs, 1H).

[1504] Step B:(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, 2H), 7.38-7.42 (m,2H), 7.23-7.38 (m, 5H), 6.60-6.61 (m, 1H), 6.34 (d, 1H), 4.37 (d, 4H),3.69 (s, 3H), 3.63 (s, 2H), 2.89 (s, 3H); MS 436 (M⁺+23).

[1505] Step C:(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-acteticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, 2H), 7.37 (t, 2H), 7.22-7.33(m, 5H), 6.57 (d, 1H), 6.31 (d, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 3.64(s, 2H), 2.87 (s, 3H). 398 MS (M⁺−1).

Example 144(3-{[(3-Hydroxy-4-propoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1506] Step A:{3-[(3-Hydroxy-4-propoxy-benzylamino)-methyl]-phenyl}-acetic acid methylester. ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.30 (m, 3H), 7.16 (d, 1H), 6.91(s, 1H), 6.79 (s, 2H), 3.98 (t, 2H), 3.77 (s, 2H), 3.70 (s, 2H), 3.68(s, 3H), 3.61 (s, 2H), 1.82 (q, 2H), 1.03 (t, 3H); MS 365 (M⁺+22).

[1507] Step B:(3-{[Methanesulfonyl-(3-methanesulfonyloxy-4-propoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.17 (m, 6H), 6.93 (d,1H), 4.28 (s, 2H), 4.23 (s, 2H), 3.97 (t, 2H), 3.68 (s, 3H), 3.61 (s,2H), 3.16 (s, 3H), 2.78 (s, 3H), 1.82 (m, 2H), 1.03 (t, 3H).

[1508] Step C:(3-{[(3-Hydroxy-4-propoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.20 (m, 4H), 6.84-6.78 (m, 3H),4.31 (s, 2H), 4.20 (s, 2H), 3.98 (t, 2H), 3.65 (s, 2H), 2.76 (s, 3H),1.83 (m, 2H), 1.04 (t, 3H).

Example 145[3-({[2-(4-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1509] MS 414 (M+).

Example 146(3-{[Methanesulfonyl-(4-phenethylsulfanyl-benzyl)-amino]-methyl}phenyl)-aceticacid

[1510] Step A:(3-{[(4-Phenethylsulfanyl-benzyl)-amino]-methyl}-phenyl)-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.33 (m, 13H), 3.78 (d,4H), 3.68 (s, 3H), 3.61 (s, 2H), 3.12-3.16 (m, 2H), 2.89-2.93 (m, 2H);MS 406 (M+1).

[1511] Step B:(3-{[Methanesulfonyl-(4-phenethylsulfanyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.31 (m, 13H), 4.30(d, 4H), 3.69 (s, 3H), 3.61 (s, 2H), 3.13-3.19 (m, 2H), 2.84-2.94 (m,2H), 2.78 (s, 3H); MS 505 (M+22).

[1512] Step C:(3-{[Methanesulfonyl-(4-phenethylsulfanyl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.29 (m, 13H), 4.27 (d, 4H), 3.61(s, 2H), 3.12-3.16 (m, 2H), 2.88-2.92 (m, 2H), 2.76 (s, 3H); MS 468(M−1).

Example 147[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1513] Step A:[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.33 (m, 4H), 7.15 (d,2H), 7.03-7.04 (m, 2H), 6.88-6.90 (m, 1H), 6.84 (s, 2H), 3.78 (d, 4H),3.66 (s, 3H), 3.59 (s, 2H), 1.82 (bs, 1H).

[1514] Step B:[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 6.81-7.17 (m, 11H), 4.31(d, 4H), 3.65 (s, 3H), 3.58 (s, 2H), 2.80 (s, 3H).

[1515] Step C:[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.07-7.35 (m, 8H), 6.92-6.93 (m, 2H),6.82 (s, 1H), 4.32 (d, 4H), 3.62 (s, 2H), 2.81 (s, 3H).

Example 148(3-{[Methanesulfonyl-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1516] Step A:(3-{[(4-Pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid methylester. ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, 2H), 8.37 (d, 2H), 7.44 (d,2H), 7.23-7.29 (m, 3H), 7.14-7.16 (m, 2H), 3.86 (s, 2H), 3.79 (s, 2H),3.66 (s, 2H), 3.60 (s, 2H); MS 348 (M+1).

[1517] Step B:(3-{[Methanesulfonyl-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 2H), 8.43 (s, 2H),7.44-7.49 (m, 2H), 7.23-7.33 (m, 5H), 4.37-4.41 (m, 4H), 3.71 (s, 3H),3.61-3.68 (m, 2H), 2.82 (s, 3H); MS 426 (M+1).

[1518] Step C:(3-{[Methanesulfonyl-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, 2H), 8.15 (d, 2H), 7.30 (d,2H), 7.24-7.27 (m, 3H), 7.15-7.17 (m, 1H), 7.03 (s, 1H), 4.42 (s, 2H),4.37 (s, 2H), 3.52 (s, 2H), 2.90 (s, 3H).

Example 149(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1519] Step A:(3-{[(4-Thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid methylester. ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.91 (m, 3H), 7.38-7.40 (m, 2H),7.22-7.29 (m, 4H), 7.14-7.16 (m, 1H), 3.82 (s, 2H), 3.78 (s, 2H), 3.66(s, 3H), 3.59 (s, 2H); MS 353 (M+1).

[1520] Step B:(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, 2H), 7.84 (d, 1H),7.17-7.37 (m, 7H), 4.33 (d, 4H), 3.67 (s, 3H), 3.59 (s, 2H), 2.80 (s,3H); MS 431 (M+1).

[1521] Step C:(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 6.98-7.85 (m, 10H), 4.30-4.40 (d, 4H),3.45 (s, 2H), 2.82 (s, 3H); MS 415 (M−1).

Example 150(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1522] Step A:(3-{[(4-Benzyl-3-hydroxy-benzyl)-amino]-methyl}-phenyl)-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.43 (m, 11 H), 7.16 (d,1H), 6.93 (d, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 3.68 (s, 3H), 3.61 (s,2H); MS 376 (M+1).

[1523] Step B:(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.43 (m, 12H), 6.94(d, 2H), 4.30 (s, 2H), 4.26 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.75(s, 3H); MS 475 (M+22).

[1524] Step C:(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.43 (m, 12H), 6.93 (d, 2H), 4.29(s, 2H), 4.25 (s, 2H), 3.64 (s, 2H), 2.74 (s, 3H); MS 438 (M−1).

Example 151(3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1525] Step A:(3-{[(4-Pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid methylester. ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.60 (s, 1H), 7.96-7.98(m, 2H), 7.46-7.48 (m, 2H), 7.11-7.30 (m, 4H), 3.77-3.88 (m, 4H),3.58-3.69 (m, 5H); MS 348 (M+1).

[1526] Step B:(3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.63-8.64 (m,1H), 8.52 (d, 1H), 8.00 (d, 2H), 7.46 (d, 2H), 7.21-7.34 (m, 4H), 4.41(s, 2H), 4.36 (s, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 2.83 (s, 3H); MS 426(M+1).

[1527] Step C:(3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.61-8.62 (m, 1H),8.56-8.57 (m, 1H), 7.78 (d, 2H), 7.34 (d, 2H), 7.16-7.30 (m, 3H), 7.05(s, 1H), 4.42 (s, 2H), 4.38 (s, 2H), 3.52 (s, 2H), 2.91 (s, 3H); MS 410(M−1).

Example 152(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1528] Step A: (3-{[(4-Phenoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.34 (m, 7H),7.17-7.19 (m, 2H), 7.06-7.11 (m, 2H), 6.96-7.00 (m, 4H), 3.79 (d, 4H),3.69 (s, 3H), 3.63 (s, 2H); MS 362 (M+1).

[1529] Step B:(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.37 (m, 9H), 7.12 (t,1H), 6.95-7.01 (m, 3H), 4.32 (d, 4H), 3.69 (s, 3H), 3.62 (s, 2H), 2.79(s, 3H); 457 (M+18).

[1530] Step C:(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.36 (m, 9H), 7.12 (t, 1H),6.94-7.01 (m, 3H), 4.32 (d, 4H), 3.65 (s, 2H), 2.79 (s, 3H); MS 424(M−1).

Example 153[3-({Methanesulfonyl-[4-(4-methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid

[1531] Step A:[3-({[4-(4-Methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, 2H), 7.33 (d, 2H),7.16-7.30 (m, 4H), 3.84 (t, 2H), 3.77 (s, 4H), 3.68 (s, 3H), 3.61 (s,2H), 2.59 (t, 2H), 2.31 (bs, 1H), 2.14 (t, 2H); MS 353 (MH+).

[1532] Step B:[3-({Methanesulfonyl-[4-(4-methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, 2H), 7.20-7.33 (m,6H), 4.30 (s, 4H), 3.86 (t, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.77 (s,3H), 2.61 (t, 2H), 2.17 (t, 2H).

[1533] Step C:[3-({Methanesulfonyl-[4-(4-methyl-[1,2,3]triazol-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, 2H), 7.14-7.31 (m, 5H), 7.05(s, 1H), 4.28 (d, 4H), 3.82 (t, 2H), 3.50 (s, 2H), 2.82 (s, 3H), 2.60(t, 2H), 2.13 (t, 2H).

Example 154[3-({Methanesulfonyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid

[1534] Step A:[3-({[4-(2-Oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.68 (m, 1H),7.52-7.58 (m, 2H), 7.41-7.47 (m, 2H), 7.17-7.36 (m, 4H), 3.90 (s, 2H),3.83 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 2.34 (s, 3H); MS 351 (MH+).

[1535] Step B:[3-({Methanesulfonyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H), 7.41-7.48 (m,4H), 7.25-7.30 (m, 1H), 7.17-7.20 (m, 3H), 4.36 (s, 2H), 4.14 (s, 2H),3.68 (s, 3H), 3.61 (s, 2H), 2.86 (s, 3H), 2.33 (s, 3H).

[1536] Step C:[3-({Methanesulfonyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-methyl)-phenyl]-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 7.13-7.39 (m, 8H), 4.40(s, 2H), 4.37 (s, 2H), 3.56 (s, 2H), 2.91 (s, 3H), 2.29 (s, 3H).

Example 1555-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1537] Step A:5-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. In Step A, triethylamine was replaced byN,N-diisopropylethylamine. MS 348(M+1).

[1538] Step B:5-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 443 (M+18).

[1539] Step C:5-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=3.8), 6.50-6.80 (m, 4H),4.40 (s, 2H), 3.23 (m, 2H), 2.80 (m, 2H), 1.70 (m, 2H); MS 400 (M+1),398 (M−1).

Example 156(3-{[(4-Ethoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1540]¹H NMR (400 MHz, CDCl₃) δ 7.16-7.31 (m, 6H), 6.83 (d, 2H), 4.27(s, 2H), 4.22 (s, 2H), 3.99 (q, 2H), 3.62 (s, 2H), 2.71 (s, 3H), 1.38(t, 3H); 376 (M−1).

Example 157(3-{[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1541]¹H NMR (400 MHz, CDCl₃) δ 7.14-7.37 (m, 6H), 6.66 (d, 2H), 4.27(s, 2H), 4.19 (s, 2H), 3.61 (s, 2H), 2.91 (s, 6H), 2.69 (s, 3H); 375(M−1).

Example 158(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1542]¹H NMR (400 MHz, CDCl₃) δ 7.32-7.16 (m, 8H), 4.31 (s, 2H), 4.28(s, 2H), 3.64 (s, 2H), 2.75 (s, 3H), 2.48 (m, 1H), 1.83 (m, 5H), 1.38(m, 5H).

Example 1595-{3-[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1543] Step A:5-[3-(4-Dimethylamino-benzylamino)-propyl]-thiophene-2-carboxylic acidmethyl ester. The title compound of Step A was prepared following theprocedure described in Step A of Example 141 except triethylamine wasreplaced with N,N-diisopropylethylamine.

[1544] Step B:5-{3-[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 411 (M+1).

[1545] Step C:5-{3-[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H), 7.15 (d, 2H), 6.72 (m,3H), 4.43 (s, 2H), 3.22 (m, 2H), 2.95 (s, 6H), 2.85 (m, 2H), 2.80 (s,3H), 1,82 (m, 2H); MS 395 (M−1).

Example 160(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1546] Step A: {3-[(4-Pentyl-benzylamino)-methyl]-phenyl}-acetic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.12 (m, 8H), 3.78 (s, 2H),3.76 (s, 2H), 3.68 (s, 3H), 3.61 (s, 2H), 2.57 (t, 2H), 1.59 (t, 2H),1.59 (t, 2H), 1.31 (m, 4H), 0.88 (t, 3H); MS 340 (M+1).

[1547] Step B:(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.14 (m, 8H), 4.31 (s,2H), 4.29 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.75 (s, 3H), 2.59 (t,2H), 1.59 (m, 2H), 1.31 (m, 4H), 0.88 (t, 3H).

[1548] Step C:(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.13 (m, 8H), 4.31 (s, 2H), 4.28(s, 2H), 3.66 (s, 2H), 2.75 (s, 3H), 2.58 (t, 2H), 1.59 (m, 4H), 1.31(m, 4H), 0.88 (t, 3H); MS 402 (M−1).

Example 161(3-{[(4-Isopropoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1549] Step A: {3-[(4-Isopropoxy-benzylamino)-methyl]-phenyl}-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.15 (m, 6H), 6.84 (d,2H), 4.52 (m, 1H), 3.78 (s, 2H), 3.72 (s, 2H), 3.68 (s, 3H), 3.61 (s,2H), 1.32 (d, 6H).

[1550] Step B:(3-{[(4-Isopropoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.19 (m, 6H), 6.84 (d,2H), 4.53 (m, 1H), 4.30 (s, 2H), 4.25 (s, 2H), 3.69 (s, 3H), 3.66 (s,2H), 3.62 (s, 2H), 2.75 (s, 3H), 1.32 (d, 6H).

[1551] Step C:(3-{[(4-Isopropoxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.17 (m, 6H), 6.83 (d, 2H), 4.52(m, 1H), 4.29 (s, 2H), 4.24 (s, 2H), 3.65 (s, 2H), 2.74 (s, 3H), 1.32(d, 6H); MS 390 (M−1).

Example 162(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1552] Step A: {3-[(4-Pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.95 (s, 2H), 7.52 (m,4H), 7.32-7.15 (m, 4H), 3.88 (s, 2H), 3.82 (s, 2H), 3.69 (s, 3H), 3.63(s, 2H).

[1553] Step B:(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. MS 425 (M+)

[1554] Step C:(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.95 (s, 2H), 7.52 (d,2H), 7.43 (d, 2H), 7.34-7.15 (m, 4H), 4.41 (s, 2H), 4.37 (s, 2H), 3.65(s, 2H), 2.86 (s, 3H); MS 410 (M−1).

Example 163(3-{[Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1555] Step A: Reductive Amination

[1556] (3-{[(4-Methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethylester. A solution of 4-methylbenzylamine (0.097 mL, 0.76 mmol) and(3-formyl-phenyl)-acetic acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2mL) was stirred for 3 h at room temperature. The reaction was cooled to0° C. and NaBH₄ (43 mg, 1.15 mmol) was added. After stirring at roomtemperature for 10 minutes, a 1:1 mixture of saturated aqueousNaHCO₃:H₂O was added. The product was extracted into CH₂Cl₂ (3×) and theorganic solution was dried over MgSO₄, filtered, and concentrated toyield the title compound (231 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.30(m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H), 1.25(t, 3H); MS 298 (M+1).

[1557] Step B: Sulfonamide Formation

[1558](3-{[Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. To a solution of(3-{[(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester(119 mg, 0.401 mmol) and triethylamine (0.61 mL, 0.726 mmol) in CH₂Cl₂(2 mL) at 0° C. was added methanesulfonyl chloride (0.031 mL, 0.405mmol). The reaction was stirred at room temperature for 2.5 h and 1N HClwas added. The product was extracted into CH₂Cl₂ (3×). The organicsolution was dried over MgSO₄, filtered, and concentrated in vacuo. Theproduct was purified by medium pressure chromatography (3:1hexanes:EtOAc) to provide the title compound (101.4 mg). ¹H NMR (400MHz, CDCl₃) δ 7.13-7.36 (m, 8H), 4.27-4.30 (m, 4H), 4.14 (q, 2H), 3.60(s, 2H), 2.74 (s, 3H), 2.33 (s, 3H); MS 376 (M+1).

[1559] Step C: Ester Hydrolysis

[1560] Step C:(3-{[Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-aceticacid. To a solution of(3-{[methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester (101.4 mg, 0.27 mmol) in MeOH (3 mL) was added aqueousNaOH (2N, 0.4 mL). The reaction was stirred at room temperature for 1 hand was diluted with a 1:1 mixture of 1N HCl and water. The product wasextracted into CH₂Cl₂ (3×) and the organic solution was dried overMgSO₄, filtered, and concentrated to provide the title compound (87 mg).¹H NMR (400 MHz, CDCl₃) δ 7.13-7.34 (m, 8H), 4.28 (d, 4H), 3.65 (s, 2H),2.75 (s, 3H), 2.33 (s, 2H); MS 346 (M−1).

Example 164-170

[1561] Examples 164-170 were prepared in an analogous manner to Example163 starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired sulfonamide in Step B and esterhydrolysis in Step C.

Example 164(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

[1562] Step A: {3-[(4-tert-Butyl-benzylamino)-methyl]-phenyl}-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.34 (m, 2H), 7.24-7.27(m, 5H), 7.15-7.16 (m, 1H), 4.13 (q, 2H), 3.77 (d, 4H), 3.59 (s, 2H),1.30 (s, 9H), 1.21-1.26 (m, 3H); MS 340 (M⁺+1).

[1563] Step B:(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.37 (m, 8H), 4.30 (d,4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.76 (s, 3H), 1.31 (s, 9H), 1.25 (t,3H).

[1564] Step C:(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.36 (m, 8H), 4.31 (s, 2H), 4.28(s, 2H), 3.64 (s, 2H), 2.75 (s, 3H), 1.30 (s, 9H); MS 388 (M⁺−1).

Example 165(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid

[1565] Step A: {3-[(4-tert-Butyl-benzylamino)-methyl]-phenoxy}-aceticacid methyl ester.

[1566] Step B:(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid methyl ester.

[1567] Step C:(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.36 (m, 5H), 6.84-6.95 (m, 3H),4.66 (s, 2H), 4.30 (s, 4H), 2.77 (s, 3H), 1.30 (s, 9H); MS 404 (M−1).

Example 166(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1568] Step A:(3-{[(4-Trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-acetic acidethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.36 (m, 2H), 7.14-7.16 (m,3H), 7.21-7.32 (m, 3H), 4.10-4.16 (m, 2H), 3.77 (d, 4H), 3.60 (s, 2H),1.21-1.25 (m, 3H); MS 368 (M+1).

[1569] Step B:(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.33 (m, 8H), 4.31 (d,4H), 4.14 (q, 2H), 3.58 (s, 2H), 2.81 (s, 3H), 1.25 (t, 3H); MS 446(M+1).

[1570] Step C:(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.32 (m, 8H), 4.30 (s, 4H), 3.62(s, 2H), 2.80 (s, 3H); MS 416 (M−1).

Example 167[3-({[3-(4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1571] Step A:[3-({[3-(4-Chloro-phenyl)-propyl]-amino}-methyl)-phenyl]-acetic acidethyl ester.

[1572] Step B:[3-({[3-(4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.31 (m, 6H), 6.95 (d,2H), 4.34 (s, 2H), 4.11 (q, 2H), 3.59 (s, 2H), 3.13-3.19 (m, 2H), 2.80(s, 3H), 2.49 (t, 2H), 1.74-1.82 (m, 2H), 1.23 (t, 3H); MS 424 (M+1).

[1573] Step C:[3-({[3-(4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid. MS 393.9 (M−1).

Example 168(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1574] Step A:(3-{[(3-Trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-acetic acidethyl ester

[1575] Step B:(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.40 (m, 8H), 4.33 (d,4H), 4.14 (q, 2H), 3.59 (s, 2H), 2.82 (s, 3H), 1.25 (t, 3H); MS 446(MH+).

[1576] Step C:(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-aceticacid. MS 417 (M−1).

Example 169[3-({[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1577]¹H NMR (400 MHz, CDCl₃) δ 6.98-7.37 (m, 8H), 4.32 (s, 2H), 3.60(s, 2H), 3.28 (m, 2H), 2.81-2.93 (m, 5H); 412 (M−1).

Example 170[3-({[4-(2-Benzo[1,3]dioxol-5-yl-vinyl)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid

[1578] MS 478 (M−1).

Example 171(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid

[1579] Step A: Reductive Amination

[1580] {3-[(4-Thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acidtert-butyl ester. A solution of (3-aminomethyl-phenoxy)-acetic acidtert-butyl ester (0.14 g, 0.59 mmol) and 4-thiazol-2-yl-benzaldehyde(0.105 g, 0.55 mmol) in 2 mL MeOH was stirred at room temperature for1.5 hours. After cooling to 0° C., NaBH₄ (0.033 g, 0.88 mmol) was addedand the reaction was stirred for 10 minutes. The mixture was quenchedwith aqueous saturated NaHCO₃:H₂O (1:1) and the MeOH was removed invacuo. The product was extracted into CH₂Cl₂ and the organic solutionwas dried over MgSO₄, filtered, and concentrated in vacuo to afford abrown oil. The product was purified via flash chromatography on silicagel (6/4 EtOAc/Hexanes) to afford the title compound of Step A (0.140g). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, 2H), 7.82 (s, 1H), 7.40 (d, 2H),7.23-7.38 (m, 2H), 6.94 (m, 2H), 6.78 (d, 1H), 4.49 (s, 2H), 3.80 (s,2H), 3.76 (s, 2H), 1.45 (s, 9H); MS 411 (M+1).

[1581] Step B: Sulfonamide Formation

[1582](3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid tert-butyl ester. A solution of({3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acidtert-butyl ester (0.045 g, 0.109 mmol), triethylamine (16.8 mL, 0.120mmol) and methanesulfonyl chloride (8.6 ml, 0.11 mmol) in 2 mL CH₂Cl₂was stirred at room temperature for 2 hours. The reaction was quenchedwith water. The aqueous solution was washed with CH₂Cl₂ and the organicsolution was dried over Na₂SO₄, filtered, and concentrated. The productwas purified via flash chromatography on silica gel (1/1 EtOAc/Hexanes)to afford the title compound of Step B as a clear oil. ¹H NMR (400 MHz,CDCl₃) δ 7.97 (d, 2H), 7.85 (s, 1H), 7.35 (m, 3H), 7.32 (m, 1H),6.80-6.90 (m, 3H), 4.48 (s, 2H), 4.36 (s, 2H), 4.29 (s, 2H), 2.79 (s,3H), 1.47 (s, 9H); MS 489 (M+1).

[1583] Step C: Ester Hydrolysis

[1584](3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid. A solution of(3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid tert-butyl ester (0.074 g) in 2 mL CH₂Cl₂ was cooled to 0° C. and 2mL trifluoroacetic acid was added. The reaction was stirred at roomtemperature for 2 hours. The solvent was removed by evaporationazeotroping with CH₂Cl₂ to afford the title compound (40 mg). ¹H NMR(400 MHz, CDCl₃) δ 9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s,1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H) 6.63 (s,1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431(M−1).

Examples 172-178

[1585] Examples 172-178 were prepared in an analogous manner to Example171 starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired sulfonamide in Step B and esterhydrolysis in Step C.

Example 172(3-{[Methanesulfonyl-(4-pyridin-2-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid hydrochloride salt

[1586] The TFA salt isolated in Step C was converted to the HCl salt byaddition of 2 equivalents of 1N HCl followed by removal of water anddrying in vacuo. MS 427 (M+1), 425 (M−1).

Example 1735-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1587] Step A:5-{3-[(2-Benzylsulfanyl-ethyl-amino]-propyl}-thiophene-2-carboxylic acidtert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.19-7.29 (m,5H), 6.73 (d, 1H), 3.68 (s, 2H), 2.83 (t, 2H), 2.71 (t, 2H), 2.53-2.59(m, 4H), 1.81 (t, 2H), 1.54 (s, 9H); MS 392 (M+1).

[1588] Step B:5-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.22-7.30(m, 5H), 6.74 (d, 1H), 3.71 (s, 2H), 3.23 (t, 2H), 3.06-3.15 (m, 2H),2.77-2.82 (m, 5H), 2.58 (t, 2H), 1.54 (s, 9H); MS 470 (M+1).

[1589] Step C:5-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. MS 412 (M−1).

Example 1745-(3-{[2-(Biphenyl-2-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1590] Step A:5-(3-{[2-(Biphenyl-2-yloxy)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.52 (m, 3H),7.24-7.39 (m, 5H), 6.90-7.20 (m, 2H), 6.69 (d, 1H), 4.08 (t, 2H), 2.89(t, 2H), 2.74 (t, 2H), 2.57 (t, 2H), 2.22 (bs, 1H), 1.71-1.79 (m, 2H),1.55 (s, 9H); MS 438 (M+1).

[1591] Step B:5-(3-{[2-(Biphenyl-2-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2carboxylicacid tert-butyl ester. MS 460 (M−56).

[1592] Step C:5-(3-{[2-(Biphenyl-2-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. MS 458 (M−1).

Example 1755-(3-{[3-(1H-Indol-3-yl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1593] Step A:5-(3-{[3-(1H-Indol-3-yl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.49-7.57(m, 2H), 7.32 (d, 1H), 7.07-7.18 (m, 2H), 6.96 (s, 1H), 6.71 (d, 1H),2.68-2.81 (m, 8H), 1.91-2.06 (m, 4H), 1.54 (s, 9H); MS 399 (M+1).

[1594] Step B:5-(3-{[3-(1H-indol-3-yl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (bs, 1H),7.50-7.55 (m, 2H), 7.34-7.36 (m, 1H), 7.08-7.20 (m, 2H), 6.98-6.99 (m,1H), 6.70 (d, 1H), 3.66 (s, 2H), 3.15-3.25 (m, 4H), 3.05-3.11 (m, 1H),2.73-2.85 (m, 6H), 1.88-2.04 (m, 4H), 1.55 (s, 9H); MS 475 (M−1).

[1595] Step C:5-(3-{[3-(1H-Indol-3-yl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. MS 419 (M−1).

Example 1765-{3-[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1596] Step A:5-{3-[(4-tert-Butyl-benzyl-amino]-propyl}-thiophene-2-carboxylic acidtert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, 1H), 7.33 (d, 2H),7.23-7.25 (m, 2H), 6.72 (d, 1H), 3.74 (s, 2H), 2.87 (t, 2H), 2.69 (t,2H), 1.90 (t, 2H), 1.54 (s, 9H), 1.29 (s, 9H); MS 388 (M+1).

[1597] Step B:5-{3-[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.49 (m, 2H),7.34-7.36 (m, 2H), 7.23-7.25 (m, 2H), 6.59 (d, 1H), 4.33 (s, 2H), 3.21(t, 2H), 2.81 (s, 3H), 2.73 (t, 2H), 1.83 (t, 2H), 1.54 (s, 9H), 1.30(s, 9H); MS 483 (M+18).

[1598] Step C:5-{3-[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, 1H), 7.36 (d, 1H), 7.25-7.26(m, 2H), 6.66 (d, 1H), 4.34 (s, 2H), 3.23 (t, 2H), 2.82 (s, 3H), 2.77(t, 2H), 1.79-1.87 (m, 2H), 1.30 (s, 9H); MS 408 (M−1).

Example 1775-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1599] Step A:5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.53 (m, 1H),7.12-7.31 (m, 4H), 6.74 (d, 1H), 3.06 (t, 2H), 2.85 (q, 4H), 2.65 (t,2H), 1.80-1.87 (m, 2H), 1.55 (s, 9H); MS 412 (MH⁺).

[1600] Step B:5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.14-7.31(m, 4H), 6.75 (d, 1H), 3.31-3.35 (m, 2H), 3.21 (t, 2H), 3.11-3.15 (m,2H), 2.82-2.87 (m, 2H), 2.82 (s, 3H), 1.94 (t, 2H), 1.54 (s, 9H); MS 508(M+18).

[1601] Step C:5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 1H), 7.31 (s, 1H), 7.15-7.25(m, 3H), 6.97 (d, 1H), 3.34-3.42 (m, 2H), 3.24 (t, 2H), 3.14 (t, 2H),2.91 (t, 2H), 2.85 (s, 3H), 1.93-2.10 (m, 2H); MS 434 (M+1).

Example 178(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid

[1602] Step A: {3-[(4-Pyridin-3-yl-benzylamino)-methyl]-phenoxy}-aceticacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (bs, 2H), 7.59 (d,2H), 7.47 (m, 2H), 7.41 (m, 2H), 7.22 (t, 1H), 6.94 (m, 2H), 6.78 (m,1H), 4.50 (s, 2H), 3.82 (s, 2H), 3.78 (s, 2H), 1.45 (s, 9H); MS 405(M+1).

[1603] Step B:(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid tert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ 8.83 (bs, 1H), 8.59 (m,1H), 7.85 (m, 1H), 7.55 (m, 2H), 7.40 (d, 2H), 7.36 (m, 1H), 7.24 (m,1H), 6.91 (d, 1H), 6.86 (m, 1H), 6.82 (dd, 1H), 4.49 (s, 2H), 4.39 (s,2H), 4.32 (s, 2H), 2.81 (s, 3H), 1.48 (s, 9H); MS 483 (M+1).

[1604] Step C:(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-aceticacid. MS 425 (M−1).

Example 1795-(3-{[3-(3-Bromo-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1605] Step A: Reductive Amination

[1606]5-(3-{[3-(3-Bromo-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. The title compound was prepared from5-(3-amino-propyl)-thiophene-2-carboxylic acid tert-butyl esterhydrochloride and 3-(3-bromo-phenyl)-propionaldehyde following themethod described in Step A of Example 141. ¹H NMR (400 MHz, CDCl₃) δ7.50 (d, 1H), 7.28-7.30 (m, 2H), 7.06-7.14 (m, 2H), 6.75 (d, 1H), 2.85(t, 2H), 2.65-2.78 (m, 4H), 2.60 (t, 2H), 1.92-2.04 (m, 4H), 1.52-1.54(m, 9H); MS 438 (M+).

[1607] Step B: Sulfonamide Formation

[1608]5-(3-{[3-(3-Bromo-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. The title compound was prepared from5-(3-{[3-(3-bromo-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester using the method described in Step B of Example141. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, 1H), 7.30-7.32 (m, 2H),7.07-7.16 (m, 2H), 6.74 (d, 1H), 3.15-3.20 (m, 4H), 2.84 (t, 2H), 2.80(s, 3H), 2.59 (t, 2H), 1.85-1.98 (m, 4H), 1.54 (s, 9H); MS 533 (M+17).

[1609] Step C: Ester Hydrolysis

[1610]5-(3-{[3-(3-Bromo-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. The title compound was prepared from5-(3-{[3-(3-bromo-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester using the method described in Step C of Example171. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, 1H), 7.31-7.33 (m, 2H),7.08-7.17 (m, 2H), 6.84 (d, 1H), 3.11-3.22 (m, 4H), 2.90 (t, 2H), 2.81(s, 3H), 2.60 (t, 2H), 1.82-1.99 (m, 4H); MS 458 (M−1).

Example 180

[1611] Example 180 was prepared in an analogous manner to Example 179starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired sulfonamide in Step B and esterhydrolysis in Step C.

Example 1805-(3-{(Butane-1-sulfonyl)-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid

[1612] Step A:5-(3-{[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. The title compound was prepared following theprocedure described in Step A of Example 179 exceptdiisopropylethylamine was used in place of triethylamine.

[1613] Step B:5-(3-{(Butane-1-sulfonyl)-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid tert-butyl ester. MS 531 (M+18).

[1614] Step C:5-(3-{(Butane-1-sulfonyl)-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 1H, J=4.0), 7.00-7.40 (m, 4H),6.70 (d, 1H, J=4.0), 3.25 (m, 4H), 2.82 (m, 2H), 2.60 (m, 2H), 1.60-2.25(m, 6H), 1.07 (t, 3H, J=7.0); MS 457 (M−1).

Example 1815-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid

[1615] Step A: Reductive Amination

[1616]5-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. Step A was performed in an analogous manner to Step Aof Example 163.

[1617] Step B: Amide Formation

[1618]5-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. A solution of5-{3-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester (0.435 g, 0.125 mmol), DCC (0.0284 g 0.137 mmol) andcyclopropanecarboxylic acid (0.0119 g, 0.137 mmol) in 10 mL CH₂Cl₂ wasstirred at room temperature for 16 h. The mixture was filtered and themother liquor was concentrated in vacuo. The residue was dissolved in 15mL EtOAc and was filtered. The organic solution was washed with waterfollowed by brine, dried over MgSO₄, filtered, and concentrated in vacuoto afford the title compound of Step B as an oil (53 mg). MS 416 (M+).

[1619] Step C: Ester Hydrolysis

[1620]5-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylicacid. Step C was performed in an analogous manner to Step C of Example141. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (bs, 1H), 6.50-7.00 (m, 4H), 4.50(s, 2H), 4.20 (bs, 4H), 3.32 (m, 2H), 2.70 (m, 2H), 1.70-1.80 (m, 2H),1.00-0.70 (m, 4H); MS 402 (M+1), 400 (M−1).

Examples 182-184

[1621] Examples 182-184 were prepared in an analogous manner to Example181 starting with the appropriate aldehyde and amine reagents in Step Afollowed by formation of the desired amide in Step B and esterhydrolysis in Step C.

Example 1825-[3-(Benzofuran-2-ylmethyl-cyclopropanecarbonyl-amino)-propyl]-thiophene-2-carboxylicacid

[1622]¹H NMR (400 MHz, CDCl₃) δ 7.70 (bs, 1H), 7.00-7.60 (m, 4H),6.60-6.95 (m, 2H), 4.60 (s, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 1.80 (m,2H), 1.00-0.70 (m, 4H); MS 384 (M+1), 382 (M−1).

Example 1835-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-thiophene-2-carboxylicacid

[1623]¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, 1H), 7.30-7.00 (m, 4H), 6.73(d, 1H), 3.20 (m, 4H), 2.92 (m, 2H), 2.71 (m, 2H), 2.20 (m, 2H),1.89-1.70 (m, 4H), 1.20 (t, 3H); MS 392 (M−1).

Example 1845-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid

[1624] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 352 (M+1).

[1625] Step B:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 394 (M+1).

[1626] Step C:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=4.0), 7.00-7.60 (m, 4H),6.80 (d, 1H, J=4.0), 3.25 (m, 4H), 2.82 (m, 2H), 2.60 (m, 2H), 2.20 (s,3H), 1.60-2.00 (m, 2H); MS 378 (M−1), 380 (M+1).

Example 1855-{3-[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid

[1627] Step A: Reductive Amination

[1628] 5-{3-[(4-Butyl-benzyl)-amino]-propyl}-thiophene-2-carboxylic acidmethyl ester. A mixture of 4-butylbenzaldehyde (250 mg, 1.541 mmol),5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl esterhydrochloride (403 mg, 1.695 mmol), and Na₂SO₄ (2.189 g, 15.41 mmol) inMeOH (10 mL) was heated at reflux for 4.5 h and additional Na₂SO₄ (2.19g) was added. The reaction was heated at reflux for 1 h and was cooledto room temperature. The solids were filtered off with the aid of MeOHand the volatiles were removed in vacuo. The residue was dissolved inTHF (10 mL) and CH₂Cl₂ (10 mL) and the solution was cooled to 0° C.Acetic acid (185 mg, 3.082 mmol) was added followed by sodiumtriacetoxyborohydride (653 mg, 3.082 mmol) and the reaction was stirredat room temperature for 16 h. The reaction was diluted with EtOAc andthe organic solution was washed with aqueous NaHCO₃ followed by brine.The organic solution was dried over MgSO₄, filtered, and concentrated.Purification by flash chromatography (99:1 CHCl₃:MeOH to 97.5:2.5CHCl₃:MeOH) provided the title compound (309 mg). MS 346 (MH+).

[1629] Step B: Sulfonamide Formation

[1630]5-{3-[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. The title compound was prepared using the methoddescribed in Step B of Example 141 except N-methylmorpholine was used inplace of triethylamine.

[1631] Step C: Ester Hydrolysis

[1632]5-{3-[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid. The title compound was prepared using the method described in StepC of Example 141. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 1H, J=4.0),7.00-7.40 (m, 4H), 6.70 (d, 1H), J=4.0), 3.22 (t, 2H, J=6.8), 2.65 (t,2H, J=6.8), 1.60-2.25 (m, 6H), 1.02-1.10 (m, 6H); MS 436 (M−1), 438(P+1).

Example 186(3-{[(Benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid

[1633] Step A: Sulfonamide Formation

[1634](3-{[(Benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. Benzofurazan-4-sulfonyl chloride (109 mg, 0.50 mmol)was added to a solution of{3-[(4-butyl-benzylamino)-methyl]-phenyl}-acetic acid methyl ester (163mg, 0.50 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) in1,2-dichloroethane. The reaction mixture was stirred at room temperaturefor 20 h. The reaction was diluted with EtOAc and the organic solutionwas washed with water followed by brine. The organic solution was driedover MgSO₄, filtered, and concentrated to afford(3-{[(benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, 1H), 7.88 (d, 1H),7.37-7.41 (m, 1H), 7.06-7.10 (m, 2H), 6.90-6.97 (m, 6H), 4.56 (s, 2H),4.51 (s, 2H), 3.66 (s, 3H), 3.45 (s, 2H), 2.48 (t, 2H), 1.45-1.53 (m,2H), 1.23-1.32 (m, 2H), 0.89 (t, 3H); MS 508 (M+18).

[1635] Step B: Ester Hydrolysis

[1636](3-{[(Benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-aceticacid. The title compound was prepared via hydrolysis of(3-{[(benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methylester following the procedure described in Step C of Example 138. ¹H NMR(400 MHz, CDCl₃) δ 7.93 (d, 1H), 7.87 (d, 1H), 7.34-7.38 (m, 1H),7.07-7.09 (m, 2H), 6.90-6.96 (m, 6H), 4.54 (s, 2H), 4.49 (s, 2H), 3.47(s, 2H), 2.46 (t, 2H), 1.44-1.51 (m, 2H), 1.21-1.31 (m, 2H), 0.88 (t,3H); MS 492 (M−1).

Examples 187-188

[1637] Examples 187-188 were prepared in an analogous manner to Example186 via sulfonamide formation from the appropriate amine in Step Afollowed by ester hydrolysis in Step B.

Example 187(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid

[1638] Step A:(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 4.30 (d, 4H), 3.69 (s, 3H),3.61 (s, 2H), 2.82-2.86 (m, 2H), 2.59 (t, 2H), 1.78-1.84 (m, 2H), 1.58(t, 2H).

[1639] Step B:(3-{[(4-Butyl-benzyl)-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.32 (m, 8H), 4.30 (d, 4H), 3.64(s, 2H), 2.81-2.90 (m, 2H), 2.59 (t, 2H), 1.74-1.83 (m, 2H), 1.54-1.61(m, 2H), 1.31-1.40 (m, 2H), 0.87-0.97 (m, 6H); MS 416 (M⁺−1).

Example 188(3-{[(4-Butyl-benzyl)-(thiophene-2-sulfonyl)-amino]-methyl}-phenyl)-aceticacid

[1640] Step A:(3-{[(4-Butyl-benzyl)-(thiophene-2-sulfonyl)-amino]-methyl}-phenyl)-aceticacid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.57 (m, 2H),7.12-7.20 (m, 2H), 6.95-7.08 (m, 7H), 4.30 (d, 4H), 3.68 (s, 3H), 3.52(s, 2H), 2.55 (t, 2H), 1.51-1.58 (m, 2H), 1.27-1.36 (m, 2H), 0.91 (t,3H); MS 472 (M+1).

[1641] Step B:(3-{[(4-Butyl-benzyl)-(thiophene-2-sulfonyl)-amino]-methyl}-phenyl)-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.54 (m, 2H), 7.10-7.18 (m, 2H),6.89-7.05 (m, 7H), 4.27 (d, 4H), 3.52 (s, 2H), 2.52 (t, 2H), 1.48-1.56(m, 2H), 1.21-1.34 (m, 2H), 0.89 (t, 3H); MS 456 (M−1).

Example 1893-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoicacid

[1642] Step A: Sulfonamide Formation

[1643]3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoicacid methyl ester. To a solution of3-(3-{[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-benzoic acid methylester (50.3 mg, 0.145 mmol) and triethylamine (32.4 mg, 0.32 mmol) inCH₂Cl₂ (10 mL) was added methanesulfonyl chloride (18.3 mg, 0.16 mmol)at 0° C. The reaction mixture was stirred for 24 h at room temperatureand was diluted with CH₂Cl₂. The organic solution was washedconsecutively with aqueous HCl (5.5%, 1×), H₂O (1×), NaHCO₃ (1×) andbrine (1×). The organic solution was dried over MgSO₄, filtered, andconcentrated to afford the title product of Step A as an oil (71 mg). MS424 (M+1).

[1644] Step B: Ester Hydrolysis

[1645]3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoicacid. The title compound was prepared via hydrolysis of3-(3-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoicacid methyl ester following the procedure described in Step C of Example141. ¹H NMR (400 MHz, CDCl₃) δ 7.00-8.00 (m, 8H), 3.19 (m, 4H), 3.00 (s,3H), 2.70 (m, 2H), 2.60 (m, 2H), 1.79-2.03 (m, 4H); MS 408 (M−1), 410(M+1).

Examples 190-197

[1646] Examples 190-197 were prepared in an analogous manner to Example189 via sulfonamide formation from the appropriate amine in Step Afollowed ester hydrolysis in Step B.

Example 1905-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

[1647] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 414 (M+1).

[1648] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.75-7.50 (m, 5H), 6.20 (d, 1H, J=4),2.95 (s, 3H), 2.80 (m, 2H), 2.65 (m, 2H), 1.80-2.00 (m, 4H); MS 398(M−1), 400 (M+1).

Example 1915-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-tetrahydrofuran-2-carboxylicacid

[1649] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-tetrahydrofuran-2-carboxylicacid methyl ester. MS 418 (M+1).

[1650] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-tetrahydrofuran-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-7.30 (m, 14H), 3.20 (t, 2H, J=6.8),2.85 (s, 3H), 2.65 (t, 2H, J=6.7), 1.90 (m, 2H); MS 402 (M−1), 404(M+1).

Example 1925-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-furan-2-carboxylicacid

[1651] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 428 (M+1).

[1652] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.70 (m, 5H), 6.21 (d, 1H, J=4),3.22 (m, 4H), 2.81 (m, 2H), 2.62 (m, 2H), 1.80-2.20 (m, 6H), 1.05 (t,3H, J=7); MS 412 (M−1), 414 (M+1).

Example 1935-{3-[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid

[1653] Step A:5-{3-[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 457 (M+18).

[1654] Step B:5-{3-[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=3.9), 7.00-7.40 (m, 4H),6.72 (d, 1H, J=3.8), 3.22 (t, 2H, J=6.9), 2.60 (t, 2H, J=7.0), 1.72-2.30(m, 6H), 1.03-1.09 (m, 6H); MS 422 (M−1).

Example 1945-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1655] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 461 (M+18).

[1656] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.62-7.71 (m, 6H), 3.26 (m, 4H), 2.83(m, 2H), 2.63 (m, 2H), 1.60-2.25 (m, 6H), 1.06 (t, 3H, J=7.0); MS 428(M−1), 429 (M+1).

Example 1953-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-benzoicacid

[1657] Step A:3-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-benzoicacid methyl ester. MS 438 (M+1).

[1658] Step B:3-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-benzoicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.00-8.00 (m, 8H), 3.21 (m, 4H), 2.78(m, 2H), 2.50 (m, 2H), 1.82-2.20 (m, 6H), 1.05 (t, 3H, J=7.0); MS 422(M−1), 424 (M+1).

Example 1965-{3-[[3-(3-Chloro-phenyl)-propyl]-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid

[1659] Step A:5-{3-[[3-(3-Chloro-phenyl)-propyl]-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid methyl ester. MS 476 (M+18).

[1660] Step B:5-{3-[[3-(3-Chloro-phenyl)-propyl]-(propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=4.0), 7.00-7.30 (m, 4H),6.80 (d, 1H, J=4.0), 3.20 (m, 4H), 2.70 (m, 4H), 2.50 (m, 2H), 1.70-2.00(m, 6H), 1.00 (t, 3H, J=7.0); MS 444 (M+1), 442 (M−1).

Example 1975-{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid

[1661] Step A: Sulfonamide Formation

[1662]5-{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester. The title compound of Step A was prepared fromthe appropriate starting materials in an analogous manner to the methoddescribed in Step A of Example 189.

[1663] Step B: Ester Hydrolysis

[1664]5-{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid. The title compound was prepared via hydrolysis of5-{3-[[3-(3-chloro-phenyl)-propyl]-(3-chloro-propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester in an analogous manner to the method described inStep C of Example 171. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.72 (m, 6H), 3.19(m, 4H), 2.79 (m, 2H), 2.60 (m, 2H), 1.60-2.20 (m, 6H); MS 477 (M−1).

Example 1985-(3-{[3-(3-Chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid

[1665] Step A: Amide Formation

[1666]5-(3-{[3-(3-Chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. A solution of5-(3-{[3-(3-chloro-phenyl)-propyl]}-propyl)-thiophene-2-carboxylic acidmethyl ester (80.7 mg, 0.23 mmol), acetoxyacetic acid (30 mg, 0.25 mmol)and DCC (52 mg, 025 mmol) in CH₂Cl₂ (10 mL) was stirred for 24 h at roomtemperature. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was dissolved in EtOAc (15 mL) and wasfiltered. The filtrate was washed consecutively with HCl (5.5%, 1×), H₂O(1×), NaHCO₃ (1×), brine (1×). The organic solution was dried overMgSO₄, filtered, and concentrated to afford the product as an oil (90mg). MS 452 (M+1).

[1667] Step B: Ester Hydrolysis

[1668]5-(3-{[3-(3-Chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid. The title compound was prepared via hydrolysis of5-(3-{[3-(3-chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester in an analogous manner to the method described in StepC of Example 141. ¹H NMR (400 MHz, CDCl₃) δ 6.70-7.80 (m, 6H), 3.24 (m,4H), 2.81 (m, 2H), 2.60 (m, 2H), 1.20-2.02 (m, 4H); MS 394 (M−1), 396(M+1).

Examples 199-205

[1669] Examples 199-205 were prepared in an analogous manner to Example198 via amide formation from the appropriate amine in Step A followed byester hydrolysis in Step B

Example 1995-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1670] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl-thiophene-2-carboxylicacid methyl ester.

[1671] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.80 (m, 6H), 3.25 (m, 4H), 2.75(m, 2H), 2.60 (m, 2H), 1.80-2.00 (m, 4H), 0.70-1.00 (m, 4H); MS 404(M−1), 406 (M+1).

Example 2005-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobutanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid

[1672] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobutanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid methyl ester.

[1673] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobutanecarbonyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.70 (m, 6H), 3.22 (m, 4H), 2.86(m, 2H), 2.66 (m, 2H), 1.66-1.99 (m, 10H); MS 418 (M−1), 420 (M−1).

Example 2015-(3-{[3-(3-Chloro-phenyl)-propyl]-methoxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid

[1674] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methoxacetyl-amino}-propyl)-thiophene-2-carboxylicacid.

[1675] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-methoxyacetyl-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.60-7.82 (m, 6H), 3.25 (m, 4H), 3.20(s, 3H), 2.80 (t, 2H, J=7.0), 2.60 (t, 2H, J=7.0), 1.60-2.00 (m, 4H); MS408 (M−1), 410 (M+1).

Example 2025-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid

[1676] Step A:5-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid methyl ester. MS 422 (M+1).

[1677] Step B:5-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.66-7.70 (m, 6H), 3.20 (m, 4H), 2.81(m, 2H), 2.62 (m, 2H), 1.70-2.20 (m, 6H), 1.04 (t, 3H, J=6.7); MS 408(M+1), 406 (M−1).

Example 2035-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-furan-2-carboxylicacid

[1678] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 392 (M+1).

[1679] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.70 (m, 5H), 6.21 (d, 1H, J=3.9),3.20 (m, 4H), 2.83 (m, 2H), 2.60 (m, 2H), 1.80-2.20 (m, 6H), 1.04 (t,3H, J=6.8); MS 376 (M−1), 378 (M+1).

Example 2045-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylicacid

[1680] Step A:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 404 (M+1).

[1681] Step B:5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.80-7.40 (m, 5H), 6.19 (d, 1H, J=4.0),3.25 (m, 4H), 2.81 (m, 2H), 2.60 (m, 2H), 1.60-2.00 (m, 4H); MS 388(M−1), 390 (M+1).

Example 2055-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-furan-2-carboxylicacid

[1682] Step A:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-furan-2-carboxylicacid methyl ester. MS 378 (M+1).

[1683] Step B:5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-furan-2-carboxylicacid. ¹H NMR (400 MHz, CDCl₃) δ 6.82-7.70 (m, 5H), 6.20 (d, 1H, J=4),3.20 (m, 4H), 2.80 (m, 2H), 2.60 (m, 2H), 2.10 (s, 3H), 1.60-2.04 (m,4H); MS 362 (M−1), 364 (M+1).

Example 2065-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid sodium salt

[1684] To a solution of5-(3-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid (7.378 g, 17.74 mmol) in MeOH (325 mL) and water (25 mL) was addedNaHCO₃ (1.490 g, 17.74 mmol) and the reaction was stirred at roomtemperature for 3 h. The reaction was concentrated in vacuo and theresidue was azeotroped with MeOH (2×50 mL) followed by CHCl₃ (2×50 mL)to provide the sodium salt as a white solid (7.661 g). ¹H NMR (400 MHz,CD₃OD) δ 7.35 (d, 1H), 7.28 (m, 2H), 7.14 (m, 2H), 6.73 (d, 1H), 3.23(m, 4H), 2.83 (s, 3H), 2.82 (m, 2H), 2.62 (t, 2H), 1.94 (m, 2H), 1.88(m, 2H).

Examples 207-216

[1685] Following the general procedure described for Example 206, thefollowing sodium salts (Examples 207-216) were prepared with variationsas noted.

Example 207

[1686](3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acidsodium salt Following the procedure described for Example 206 the sodiumsalt was generated. The sodium salt was stirred in 3% EtOH/EtOAc at 45°C. for 20 h, was cooled to room temperature and was filtered to providea white solid. mp 158° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.26-7.11 (m, 8H),4.28 (s, 4H), 3.45 (s, 2H), 3.29 (s, 2H), 2.80 (s, 3H), 2.58 (t, 2H),1.57 (m, 2H), 1.33 (m, 2H), 0.92 (t, 3H).

Example 208[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid sodium salt

[1687]¹H NMR (400 MHz, CD₃OD) δ 7.29-7.21 (m, 4H), 6.94 (m, 2H), 6.84(d, 1H), 6.44 (d, 1H), 6.24 (m, 1H), 4.37 (s, 2H), 4.35 (s, 2H), 3.94(d, 2H), 2.94 (s, 3H).

Example 209[3-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenoxy]-aceticacid sodium salt

[1688]¹H NMR (400 MHz, CD₃OD) δ 7.21 (m, 1H), 6.96 (m, 3H), 6.83 (m,3H), 4.44 (s, 2H), 4.35 (s, 2H), 4.01 (t, 2H), 3.56 (t, 2H), 2.97 (s,3H).

Example 2102-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid sodium salt

[1689]¹H NMR (400 MHz, CD₃OD) δ 7.82 (bs, 1H), 6.99 (m, 1H), 6.92 (m,2H), 4.15 (t, 2H), 3.62 (m, 2H), 3.36 (m, 2H), 3.03 (m, 2H), 2.94 (s,3H), 2.14 (m, 2H).

Example 211N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamidesodium salt

[1690]¹H NMR (400 MHz, CD₃OD) δ 7.00 (s, 1H), 6.93 (s, 2H), 4.14 (t,2H), 3.58 (t, 2H), 3.23 (t, 2H), 2.91 (s, 3H), 2.80 (t, 2H), 1.73 (m,2H), 1.62 (m, 2H), 1.36 (m, 4H).

Example 2127-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid sodium salt

[1691] Following the procedure described for Example 206 the sodium saltwas generated. The sodium salt was stirred in 2% water in EtOAc at 65°C. for 20 h. The mixture was cooled to room temperature and was filteredto provide a white solid. mp 166° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.00 (s,1H), 6.94 (s, 2H), 4.14 (t, 2H), 3.59 (t, 2H), 3.29 (t, 2H), 2.92 (s,3H), 2.14 (t, 2H), 1.60 (m, 4H), 1.35 (m, 4H).

Example 213 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acidsodium salt

[1692] Following the procedure described for Example 206 the sodium saltwas generated. The sodium salt was stirred in 10% EtOH in EtOAc at 65°C. for 20 h. The mixture was cooled to room temperature and was filteredto provide a white solid. mp 137° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.27 (d,2H), 7.15 (d, 2H), 4.32 (s, 2H), 3.12 (t, 2H), 2.85 (s, 3H), 2.60 (t,2H), 2.09 (t, 2H), 1.60-1.20 (m, 12H), 0.92 (t, 3H).

Example 214(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid sodium salt

[1693]¹H NMR (400 MHz, CD₃OD) δ 7.33-7.15 (m, 8H), 4.31 (s, 2H), 4.28(s, 2H), 3.64 (s, 2H), 2.74 (s, 3H), 2.48 (m, 1H), 1.84 (m, 4H), 1.74(m, 1H), 1.38 (m, 4H), 1.24 (m, 1H).

Example 215(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid sodium salt

[1694] Following the procedure described for Example 206 the sodium saltwas generated. The sodium salt was stirred in 2% water in EtOAc at 65°C. for 20 h. The mixture was cooled to room temperature and was filteredto provide a white solid. mp 184-186° C.; ¹H NMR (400 MHz, D₂O) δ 7.19(d, 2H), 7.04 (m, 3H), 6.71 (d, 1H), 6.63 (d, 1H), 6.49 (s, 1H), 4.20(s, 2H), 4.18 (s, 2H), 4.17 (s, 2H), 2.88 (s, 3H), 1.08 (s, 9H).

Example 2165-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid sodium salt

[1695]¹H NMR (400 MHz, CD₃OD) δ 7.34 (d, 1H), 6.99 (t, 1H), 6.90 (d,2H), 6.72 (d, 1H), 4.12 (t, 2H), 3.60 (t, 2H), 3.31 (t, 2H), 2.92 (s,3H), 2.83 (t, 2H), 2.00 (m, 2H).

Preparations C4-C6

[1696] Preparations C4-C6 were prepared from the appropriate startingmaterials in an analogous manner to Preparation C1.

Preparation C4 N-[3-(5-Methyl-thiophen-2-yl)-propyl]-methanesulfonamide

[1697]¹H NMR (400 MHz, CDCl₃) δ 6.57-6.53 (m, 2H), 4.35 (m, 1H), 3.17(m, 2H), 2.93 (s, 3H), 2.83 (t, 2H), 2.42 (s, 3H), 1.90 (m, 2H).

Preparation C5 [3-(3-Methanesulfonylamino-propyl)-phenyl]-acetic acidmethyl ester

[1698]¹H NMR (250 MHz, CDCl₃) δ 7.30-7.06 (m, 4H), 4.34 (m, 1H), 3.70(s, 3H), 3.61 (s, 2H), 3.27 (m, 2H), 2.94 (s, 3H), 2.72 (t, 2H), 1.93(m, 2H).

Preparation C6 [2-(3-Methanesulfonylamino-propyl)-phenyl]-acetic acidmethyl ester

[1699]¹H NMR (400 MHz, CDCl₃) δ 7.24-7.16 (m, 4H), 4.58 (m, 1H), 3.69(s, 3H), 3.66 (s, 2H), 3.17 (q, 2H), 2.94 (s, 3H), 2.72 (t, 2H), 1.88(m, 2H).

Preparations D3-D4

[1700] Preparations D3-D4 were prepared from the appropriate startingmaterials in an analogous manner to Preparation D1.

Preparation D3 1-Bromomethyl-4-propyl-benzene

[1701]¹H NMR (400 MHz, CDCl₃) δ 7.30-7.25 (m, 2H), 7.14 (m, 2H), 4.48(s, 2H), 2.56 (t, 2H), 1.62 (m, 2H), 0.93 (t, 3H).

Preparation D4 1-Bromomethyl-4-ethyl-benzene

[1702]¹H NMR (400 MHz, CDCl₃) δ 7.28 (m, 2H), 7.16 (d, 2H), 4.48 (s,2H), 2.63 (q, 2H), 1.22 (t, 3H).

Preparations F3-F4

[1703] Preparations F3-F4 were prepared from the appropriate startingmaterials in an analogous manner to Preparation F1.

Preparation F3 2-Bromo-methyl-benzofuran Preparation F46-Chloro-2-bromomethyl-quinoline Preparations L4-L17

[1704] Preparations L4-L17 were prepared from the appropriate startingmaterials in an analogous manner to Preparation L1.

Preparation L4 1-(2-Bromo-ethoxy)-3-ethyl-benzene Preparation L51-(2-Bromo-ethoxy)-3-isopropyl-benzene Preparation L61-(2-Bromo-ethoxy)-3-trifluoromethyl-benzene Preparation L71-(2-Bromo-ethoxy)-3,5-difluoro-benzene

[1705]¹H NMR (400 MHz, CDCl₃) δ 6.42 (m, 3H), 4.24 (t, 2H), 3.62 (t,2H).

Preparation L8 1-(2-Bromo-ethoxy)-3,5-dichloro-benzene Preparation L91-(2-Bromo-ethoxy)-3-fluoro-benzene Preparation L101-(2-Bromo-ethoxy)-3-chloro-5-methoxy-benzene Preparation L111-(2-Bromo-ethoxy)-3-ethoxy-benzene Preparation L121-(2-Bromo-ethoxy)-3-chloro-benzene Preparation L135-(2-Bromo-ethoxy)-benzo[1,3]dioxole

[1706]¹H NMR (400 MHz, CDCl₃) δ 6.69 (d, 1H), 6.50 (s, 1H), 6.33 (dd,1H), 5.91 (s, 2H), 4.20 (t, 2H), 3.59 (t, 2H).

Preparation L14 1-(2-Bromo-ethoxy)-3,5-bis-trifluoromethyl-benzenePreparation L15 1-(3-Bromo-propoxy)-3-chloro-5-methoxy-benzenePreparation L16 1-(3-Bromo-propoxy)-3,5-dichloro-benzene Preparation L171-(2-Bromo-ethoxy)-3-methoxy-benzene Preparation W25-(3-Oxo-propyl)-thiophene-2-carboxylic acid tert-butyl ester

[1707] Step A: Ester Formation

[1708] 5-Bromo-thiophene-2-carboxylic acid tert-butyl ester. To amixture of anhydrous MgSO₄ (11.60 g, 96.4 mmol) in 100 mL CH₂Cl₂ wasadded concentrated H₂SO₄ (1.45 mL, 24.1 mmol) and the mixture wasstirred for 15 minutes followed by addition of5-bromo-thiophene-2-carboxylic acid (5.0 g, 24.1 mmol). After stirringfor 1 minute, tert-butanol (11.6 g, 20 mmol) was added and the reactionwas stirred at room temperature for 18 h. The reaction was quenched withsaturated NaHCO₃. The layers were separated, the aqueous layer wasextracted with CH₂Cl₂, and the combined organic layers were dried overMgSO₄. The organic solution was concentrated to give a clear oil whichwas purified via medium pressure chromatography (3% EtOAc in hexanes) toafford the title compound (4.97 g). ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d,1H), 7.02 (d, 1H), 1.54 (s, 9H).

[1709] Step B: Aldehyde Formation

[1710] 5-(3-Oxo-propyl)-thiophene-2-carboxylic acid tert-butyl ester. Toa solution of 5-bromo-thiophene-2-carboxylic acid tert-butyl ester (0.50g, 1.89 mmol) in 5 mL DMF was added allyl alcohol (0.51 mL, 7.57 mmol)followed by NaHCO₃ (0.397 g, 4.72 mmol), tetrabutylammonium chloride(0.525 g, 1.89 mmol), and palladium acetate (0.021 g, 0.094 mmol). Thereaction was placed in an oil bath heated to 65° C. and was heated to90° C. for 2 h. The mixture was diluted with EtOAc and 25 mL water andthe solids were removed by filtration through Celite. The layers wereseparated, and the organic solution was washed with water (4×), driedover MgSO₄ and concentrated to a dark yellow oil which was purified viamedium pressure chromatography (7:1 hexanes:EtOAc) to afford the titlecompound (0.190 g). ¹H NMR (400 MHz, CDCl₃) δ 9.80 (s, 1H), 7.51 (d,1H), 6.78 (d, 1H), 3.14 (t, 2H), 2.86 (t, 2H), 1.54 (s, 9H).

Preparation X1 3-(2-Methanesulfonylamino-ethyl)-benzoic acid methylester

[1711] Step A

[1712] 3-Cyanomethyl-benzoic acid methyl ester. A mixture of3-bromomethyl-benzoic acid methyl ester (3.00 g, 13.10 mmol), potassiumcyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated at 40-45° C. for45 minutes and was stirred at room temperature for 18 h. The reactionwas heated at 40° C. for 24 h, was cooled to room temperature, andadditional potassium cyanide (1.02 g, 15.71 mmol) was added. Thereaction was heated at 40° C. for 18 h and was cooled to roomtemperature. Water (25 mL) was added and the product was extracted intoEtOAc (3×25 mL). The combined organic layers were washed with 1N LiClfollowed by brine, dried over MgSO₄, filtered, and concentrated. Flashchromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided3-cyanomethyl-benzoic acid methyl ester (1.36 g). MS 193 (M+18).

[1713] Step B

[1714] 3-(2-Amino-ethyl)-benzoic acid methyl ester. A solution of3-cyanomethyl-benzoic acid methyl ester (1.36 g) in EtOH (25 mL) wassaturated with HCl (g) and PtO₂ (200 mg) was added. The reaction washydrogenated on a Parr shaker at 50 psi for 2.5 h. The catalyst wasremoved via filtration through Celite and the solvent was removed invacuo. The resulting solid was stirred in Et₂O and the mixture wasfiltered to yield the title compound as a white solid (1.18 g). MS 180(M+1).

[1715] Step C

[1716] 3-(2-Methanesulfonylamino-ethyl)-benzoic acid methyl ester. To asolution of 3-(2-amino-ethyl)-benzoic acid methyl ester (500 mg) inCH₂Cl₂ (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred atroom temperature for 18 h and was washed consecutively with 5.5% HCl,water, saturated NaHCO₃, and brine. The organic solution was dried overMgSO₄, filtered, and concentrated to yield the title compound (522 mg)as a white solid. MS 275 (M+18).

Preparation Y1 (3-Formyl-phenyl)-acetic acid ethyl ester

[1717] Step A

[1718] Method A

[1719] (3-Cyano-phenyl)-acetic acid ethyl ester. To a mixture of of(3-bromo-phenyl)-acetic acid ethyl ester (15.3 g, 62.9 mmol) and1-methyl-2-pyrrolidinone (125 mL) was added copper (I) cyanide (8.46 g,94.4 mmol). The reaction mixture was stirred in an oil bath at 190° C.for 1 h. The reaction was cooled to room temperature and was dilutedwith EtOAc and 2:1 H₂O/NH₄OH. The mixture was stirred for 10 minutes andwas filtered through Celite. The aqueous layer was washed with EtOAc(2×). The organic solution was washed with 2:1 H₂O/NH₄OH until theaqueous extracts were no longer blue. The organic solution was driedover MgSO₄, filtered and concentrated to afford (3-cyano-phenyl)-aceticacid ethyl ester (11.95 g). ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.58 (m, 3H),7.43 (t, 1H), 4.16 (q, 2H), 3.63 (s, 2H), 1.25 (t, 3H).

[1720] Method B

[1721] (3-Cyano-phenyl)-acetic acid ethyl ester. A mixture of(3-bromo-phenyl)-acetic acid ethyl ester (12.38 g, 54.05 mmol), zinccyanide (4.33 g, 36.9 mmol), and DMF (150 mL) was deoxygenated withnitrogen and Pd(PPh₃)₄ (3.10 g, 2.68 mmol) was added. The mixture washeated in a 90° C. oil bath for 2.5 h and was cooled to roomtemperature. Aqueous NH₄OH (5%) was added and the product was extractedinto Et₂O (3×). The combined organic extracts were washed with 5% NH₄OHfollowed by brine. The organic solution was dried over MgSO₄, filteredand concentrated. Flash chromatography (9:1 hexanes:EtOAc) provided(3-cyano-phenyl)-acetic acid ethyl ester (9.08 g) as a pale yellowliquid which was identical spectroscopically to that obtained usingMethod A above.

[1722] Step B

[1723] (3-Formyl-phenyl)-acetic acid ethyl ester. To a solution of(3-cyano-phenyl)-acetic acid ethyl ester (4.8 g, 25.4 mmol) in 75%aqueous formic acid was added nickel-aluminum alloy (4.6 g). The mixturewas heated at reflux (100° C.) for 2.25 h. The reaction mixture wascooled and was filtered through Celite with the aid of boiling EtOH. Thefiltrate was diluted with H₂O and the product was extracted into CHCl₃(3×). The organic solution was stirred with saturated NaHCO₃ solutionuntil a pH of 8 was attained. The organic solution was dried over MgSO₄,filtered, and concentrated. The product was purified by flashchromatography (5:1 hexanes/EtOAc) to afford the title compound (3.33g). ¹H NMR (400 MHz, CDCl₃) δ 7.76-7.79 (m, 2H), 7.47-7.57 (m, 2H), 4.15(q, 2H), 3.69 (s, 2H), 1.25 (t, 3H); MS 193 (M+1).

Preparation Z1 (3-Formyl-phenyl)-acetic acid methyl ester

[1724] Step A

[1725] (3-Cyano-phenyl)-acetic acid methyl ester. Nitrogen was bubbledthrough a mixture of (3-bromo-phenyl)-acetic acid methyl ester (22.85 g,99.78 mmol), Zn(CN)₂ (7.25 g, 61.75 mmol), and DMF (100 mL) for about 5minutes followed by addition of tetrakistriphenylphosphine(0) palladium(4.60 g, 3.98 mmol). The mixture was heated for 3 h at 80° C. and wascooled to room temperature. Aqueous 2N NH₄OH was added and the productwas extracted into EtOAc (3×). The organic solution was washed with 2NNH₄OH (2×) followed by brine (2×). The organic solution was dried(MgSO₄), filtered, and concentrated in vacuo. Purification by flashchromatography (6:1 hexanes:EtOAc) provided the title compound as an oil(15.19 g). ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.41 (m, 4H), 3.706 (s, 3H),3.703 (s, 2H).

[1726] Step B

[1727] (3-Formyl-phenyl)-acetic acid methyl ester. A mixture of(3-cyano-phenyl)-acetic acid methyl ester (1.56 g, 8.91 mmol),aluminum-nickel alloy (1.63 g) and 75% formic acid (25 mL) was heated atreflux for 1.75 h. The mixture was cooled to room temperature and thesolids were removed by filtration through Celite with the aid of boilingEtOH. Water was added and the aqueous solution was washed with CH₂Cl₂(3×). Aqueous saturated NaHCO₃ was carefully added to the organicsolution until the pH was about 8-9. The organic solution was washedwith brine, dried over MgSO₄, and concentrated. Purification by flashchromatography (5:1 hexanes:EtOAc) provided the title compound as aclear and colorless oil (870 mg). ¹H NMR (400 MHz, CDCl₃) δ 9.98 (s,1H), 7.77 (m, 2H), 7.55-7.46 (m, 2H), 3.68 (s, 5H).

Preparation AA1 2-(3-Methanesulfonylamino-propyl)-thiazole-4-carboxylicacid ethyl ester

[1728] Step A

[1729] 4-Methanesulfonylamino-butyric acid ethyl ester. Methanesulfonylchloride (4.10 g, 35.8 mmol) was added to a suspension of ethyl4-aminobutyrate hydrochloride (6.00 g, 35.8 mmol) and Et₃N (10.8 mL,77.4 mmol) in THF (230 mL). The resulting suspension was stirred at roomtemperature for 43 h. The reaction mixture was filtered and the filtratewas concentrated. Flash chromatography (1:1 EtOAc:hexanes to EtOAc)afforded the title compound (7.08 g). ¹H NMR (400 MHz, CDCl₃) δ 4.51 (s,1H), 4.12 (q, 2H), 3.18 (q, 2H), 2.94 (s, 3H), 2.40 (t, 2H), 1.85-1.92(m, 2H), 1.24 (t, 3H); MS 210 (M⁺+1).

[1730] Step B

[1731] 4-Methanesulfonylamino-butyramide. A solution of4-methanesulfonylamino-butyric acid ethyl ester (7.08 g, 33.8 mmol) inconcentrated NH₄OH (200 mL) was stirred at room temperature for 66 h.The reaction mixture was concentrated to afford the title compound as awhite solid (6.16 g). The product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 3.30 (s, 3H), 3.05-3.09(m, 2H), 2.91 (s, 3H), 2.24-2.30 (m, 2H), 1.80-1.85 (m, 2H); MS 181(M⁺+1).

[1732] Step C

[1733] 4-Methanesulfonylamino-thiobutyramide. A suspension of4-methanesulfonylamino-butyramide (0.50 g, 2.8 mmol) and Lawesson'sreagent (0.56 g, 1.4 mmol) in THF (50 mL) was stirred at roomtemperature for 45 minutes. During this time all of the solid dissolved.The solution was concentrated and purified by flash chromatography (79:1EtOAc:MeOH) to afford the title compound (0.41 g); ¹H NMR (400 MHz,CDCl₃) δ 3.29 (s, 3H), 3.07-3.11 (m, 2H), 2.91 (s, 3H), 2.62-2.66 (m,2H), 1.93-1.99 (m, 2H); MS 197 (M⁺+1).

[1734] Step D

[1735] 2-(3-Methanesulfonylamino-propyl)-thiazole-4-carboxylic acidethyl ester. A solution of 4-methanesulfonylamino-thiobutyramide (0.35g, 1.8 mmol) and ethyl bromopyruvate (0.37 g, 1.9 mmol) in EtOH (50 mL)was stirred at room temperature for 17 h. Additional ethyl bromopyruvate(0.05 g, 0.26 mmol) was added and the reaction mixture was stirred atroom temperature for 5.5 h. The reaction mixture was concentrated andwas purified by flash chromatography (79:1 to 19:1 EtOAc:MeOH) to affordthe title compound (0.47 g). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H),4.40 (q, 2H), 3.24 (t, 2H), 3.17 (t, 2H), 2.96 (s, 3H), 2.10 (t, 2H),1.39 (t, 3H); MS 293 (M⁺+1).

Preparation BB1 N-(4-Butoxy-benzyl)-methanesulfonamide

[1736] Step A: Nitrile Reduction

[1737] 4-Butoxybenzylamine. To a solution of 4-butoxybenzonitrile (4.6g, 26.25 mmol) in Et₂O (50 mL) was added lithium aluminum hydride (1.0 Min THF, 26.2 mL, 26.2 mmol) dropwise. The reaction was heated at refluxfor 1 h and was cooled to room temperature. The reaction was carefullypoured into water (50 mL) and was diluted with Et₂O. The solids wereremoved by filtration through Celite with the aid of Et₂O. The organicsolution was washed with water followed by brine, dried (MgSO₄),filtered, and concentrated in vacuo to provide 4-butoxybenzylamine (2.68g). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (m, 2H), 6.82 (m, 2H), 3.91 (m, 2H),3.75 (s, 2H), 1.73 (m, 2H), 1.46 (m, 2H), 1.39 (m, 2H), 0.95 (t, 3H).

[1738] Step B: Sulfonamide Formation

[1739] N-(4-Butoxy-benzyl)-methanesulfonamide. The title compound wasprepared following the general procedure described in Step 2 ofPreparation A1. ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, 2H), 6.86 (d, 2H),4.76 (bs, 1H), 4.23 (m, 2H), 3.94 (m, 2H), 2.83 (s, 3H), 1.75 (m, 2H),1.47 (m, 2H), 0.96 (t, 3H).

Preparation CC1 3-(3-Chloro-phenyl)-propionaldehyde

[1740] A solution of 1-chloro-3-iodobenzene (9.63 g, 40.38 mmol), allylalcohol (5.86 g, 100.96 mmol), sodium bicarbonate (8.48 g, 100.96 mmol),tetrabutylammonium chloride (11.22 g, 40.38 mmol), and Pd(OAc)₂ (317 mg,1.413 mmol) in 25 mL DMF was stirred at 50° C. for 18 h. The mixture wascooled to room temperature, diluted with water, and the aqueous solutionwas washed with EtOAc. The organic solution was washed with waterfollowed by brine, dried over MgSO₄, filtered and concentrated in vacuo.The product was purified via flash chromatography on silica gel (9:1hexanes:EtOAc) to afford the title compound as an oil (5.04 g).

Preparation CC2 3-(3-Bromo-phenyl)-propionaldehyde

[1741] The title compound was prepared using the method described abovefor Preparation CC1 with a reaction time of 1 h at 90° C.

Preparation DD1 5-(3-Amino-propyl)-thiophene-2-carboxylic acid methylester

[1742] Step A

[1743] 5-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylicacid methyl ester. A mixture of prop-2-ynyl-carbamic acid tert-butylester (1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methylester (2.50 g, 0.011 mmol), tetrakistriphenylphosphine(0) palladium(0.622 9, 0.0538 mmol), CuI (0.102 g, 0.538 mmol) and triethylamine(1.57 mL, 0.011 mmol) in 50 mL acetonitrile under nitrogen was heated atreflux for 16 h. The reaction was cooled to room temperature, dilutedwith 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried overMgSO₄, filtered and concentrated in vacuo to an oil. The product waspurified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to affordthe title compound as an oil (2.06 g). MS 313 (M+18).

[1744] Step B

[1745] 5-(3-tert-Butoxycarbonylamino-propyl)-thiophene-2-carboxylic acidmethyl ester. A mixture of5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidmethyl ester (2.06 g) and 10% palladium on carbon (1.03 g) in 50 mL MeOHwas hydrogenated on a Parr shaker at 50 psi H₂ for 16 h. The reactionwas filtered through Celite with the aid of MeOH and the filtrate wasconcentrated in vacuo to afford the title compound as a solid (1.93 g).MS 317 (M+18).

[1746] Step C

[1747] 5-(3-Amino-propyl)-thiophene-2-carboxylic acid methyl ester. Asolution of 5-(3-tert-butoxycarbonylamino-propyl)-thiophene-2-carboxylicacid methyl ester (0.118 g, 0.5 mmol) in 50 mL MeOH was cooled to 0° C.and was saturated with HCl (g). The reaction was stirred at roomtemperature for 90 minutes. The solution was concentrated to a solidwhich was partitioned between EtOAc and saturated NaHCO₃. The layerswere separated, and the organic layer was washed with brine, dried overMgSO₄, filtered and concentrated in vacuo to afford the title compoundas an oil (399 mg). MS 200 (M+1).

Preparation DD2 5-(3-Amino-propyl)-furan-2-carboxylic acid methyl esterhydrochloride salt

[1748] The title compound was prepared from the appropriate startingmaterials in an analogous manner to Preparation DD1 with the followingexceptions. The hydrogenation performed in Step B was carried out for5.5 h. In Step C, the reaction was stirred for 16 h at room temperatureand was concentrated in vacuo to provide the title compound as thehydrochloride salt.

Preparation EE1 5-(3-Amino-propyl)-thiophene-2-carboxylic acidtert-butyl ester

[1749] Step A

[1750] Prop-2-ynyl-carbamic acid benzyl ester

[1751] To a solution of propargylamine (6.4 g, 71.2 mmol) in pyridine(100 mL) was added benzylchloroformate (13.37 g, 78.2 mmol) in 100 mLCH₂Cl₂ over 0.5 h. The reaction was stirred for 16 h and the volatileswere removed in vacuo. The residue was dissolved in EtOAc and theorganic solution was washed with water (2×). The organic solution waswashed with dilute aqueous HCl followed by saturated NaHCO₃. The organicsolution was dried over MgSO₄, filtered, and concentrated in vacuo toprovide the title compound (4.43 g).

[1752] Step B

[1753] 5-(3-Benzyloxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylicacid tert-butyl ester. The title compound was prepared from theappropriate starting material in an analogous manner to Step A ofPreparation DD1.

[1754] Step C

[1755] 5-(3-Amino-propyl)-thiophene-2-carboxylic acid tert-butyl esterhydrochloride salt. To a solution of5-(3-benzyloxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acidtert-butyl ester (1.0 g, 2.69 mmol) in 15 mL MeOH and 2.69 mL 1N HCl(aq) was added Pd(OH)₂ (1 g). The mixture was shaken in a Parr shakerunder 45 psi H₂ for 16 h. The catalyst was removed by filtration throughCelite and additional Pd(OH)₂ (1 g) was added. The reaction was shakenat 45 psi H₂ for 6 h and the catalyst was removed by filtration throughCelite. The solution was concentrated in vacuo. The residue wasazeotroped with CCl₄ and was triturated with Et₂O to provide the titleamine (360 mg).

Preparation FF15-{3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-thiophene-2-carboxylicacid methyl ester

[1756] A solution of 5-(3-amino-propyl)-thiophene-2-carboxylic acidmethyl ester (0.118 g, 0.5 mmol) and diisopropylethylamine (0.071 g,0.55 mmol) in 10 mL MeOH was stirred at room temperature for 30 minutesand 3-(3-chloro-phenyl)-propionaldehyde (0.093 g, 0.55 mmol) was added.The mixture was stirred for 90 minutes. The reaction was cooled to 0°C., NaBH₄ (0.83 mL, 5.98 mmol) was added and the mixture was stirred for30 minutes. The reaction was quenched with 1:1 NaHCO₃:H₂O and was washedwith CH₂Cl₂. The CH₂Cl₂ extracts were washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo to afford the title compoundas an oil (171 mg). MS 352 (M+1).

Preparations FF2-FF4

[1757] Preparations FF2-FF4 were prepared from the appropriate startingmaterials in an analogous manner to Preparation FF1.

Preparation FF25-{3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-thiophene-2-carboxylicacid tert-butyl ester

[1758]¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, 1H), 7.25-7.05 (m, 4H), 6.74(d, 1H), 2.83 (t, 2H), 2.72-2.59 (m, 6H), 1.97-1.82 (m, 4H), 1.53 (s,9H); MS 394 (M+1).

Preparation FF35-{3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-furan-2-carboxylic acidmethyl ester MS 336 (M+1). Preparation FF45-{3-[3-(3-Chloro-phenyl)-propylamino]-propyl}-tetrahydrofuran-2-carboxylicacid methyl ester

[1759] MS 340 (M+1).

Preparation GG1 3-(3-Chloro-phenyl)-propylamine

[1760] Step A

[1761] 3-(3-Chloro-phenyl)-acrylamide. A solution of3-(3-chloro-phenyl)-acrylic acid (15.0 g, 82.15 mmol) in 50 mL thionylchloride was heated at reflux for 30 minutes. The excess thionylchloride was removed via distillation at atmospheric pressure. Theresidue was azeotroped with benzene in vacuo to give 17.288 g of anorange oil. The oil was dissolved in 25 mL CH₂Cl₂ and the solution wasadded slowly to liquid NH₃ (20 mL, 80.07 mmol) in CHCl₃ (50 mL) at −78°C. The resulting suspension was warmed to room temperature and wasconcentrated in vacuo to afford the title compound as a gray solid(19.38 g). ¹H NMR (400 MHz, CD₃OD) δ 7.57 (s, 1H), 7.45 (m, 2H), 7.36(m, 1H), 6.64 (d, 1H); MS 182 (M+1), 180 (M−1).

[1762] Step B

[1763] 3-(3-Chloro-phenyl)-propylamine. A 1.0 M solution of LiAlH₄ inTHF (6.0 mL, 6.0 mmol) was added dropwise to a suspension of3-(3-chloro-phenyl)-acrylamide (1.0 g, 5.51 mmol) in 30 mL THF at 0° C.The reaction was warmed to room temperature and was stirred for 5 h. Anadditional 4 mL of 1 M LiAlH₄ was added and the reaction was stirred for18 h. An addition 2 mL of 1 M LiAlH₄ was added and the reaction wasstirred for 24 h. The reaction mixture was quenched by dropwise additionof water. The mixture was concentrated in vacuo to remove THF and wasdiluted with water. The aqueous solution was extracted with EtOAc. Theorganic solution was washed with water, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was dissolved in CHCl₃ and theorganic solution was washed with 1M HCl. The aqueous solution wasbasified to pH 11 with 1M NaOH and the product was extracted into CHCl₃.The organic solution was dried over MgSO₄, filtered and concentrated invacuo to afford the title compound as a yellow oil (0.134 g). ¹H NMR(400 MHz, CDCl₃) δ 7.20-7.22 (m, 3H),7.16 (m, 1H), 2.74 (t, 2H), 2.61(t, 2H), 1.74 (m, 2H); MS 170 (M+1).

Preparation HH1 4-Pyrimidin-2-yl-benzaldehyde

[1764] A solution of 2-bromopyrimidine (1.00 g, 6.3 mmol) andtetrakistriphenylphosphine(0) palladium (0.218 g, 0.189 mmol) inethylene glycol dimethyl ether (30 mL) was stirred at room temperaturefor 10 minutes. A solution of 4-formylbenzene boronic acid (1.14 g, 7.61mmol) and sodium bicarbonate (1.58 g, 18.9 mmol) in 15 mL water wasadded and the reaction was heated at reflux for 18 h. The mixture wasdiluted with water and CH₂Cl₂. The layers were separated, and theaqueous solution was washed with CH₂Cl₂. The combined organic layerswere dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified via flash chromatography (10% to 30% hexanes in EtOAc) toafford the title compound (0.979 g). ¹H NMR (400 MHz, CDCl₃) δ 10.11 (s,1H), 8.83 (s, 2H), 8.82 (s, 1H), 7.98 (s, 2H), 7.23 (s, 2H).

Preparation HH2-HH7

[1765] Preparations HH2-HH7 were prepared from the appropriate startingmaterials in an analogous manner to Preparation HH1.

Preparation HH2 4-Pyridin-2-yl-benzaldehyde

[1766]¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.72 (s, 1H),8.16 (s,2H), 7.95 (s, 2H), 7.79 (s, 2H), 7.29 (m, 1H); MS 184 (M+1).

Preparation HH3 4-Pyridin-3-yl-benzaldehyde

[1767]¹H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 8.88 (s, 1H),8.64 (s,1H), 7.97 (s, 2H), 7.91 (m, 1H), 7.75 (m, 2H), 7.39 (m, 1H); MS 184(M+1).

Preparation HH4 4-Pyridin-4-yl-benzaldehyde

[1768]¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 8.70 (s, 2H),7.99 (s,2H), 7.79 (s, 2H), 7.52 (s, 2H); MS 184 (M+1).

Preparation HH5 4-Thiazol-2-yl-benzaldehyde

[1769] MS 189 (M+).

Preparation HH6 4-Pyrimidin-5-yl-benzaldehyde

[1770]¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 9.26 (s, 1H), 9.00 (s,2H), 8.03 (m, 2H), 7.76 (m, 2H).

Preparation HH7 4-Pyrazin-2-yl-benzaldehyde

[1771]¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 9.10 (s, 1H), 8.69 (s,1H), 8.59 (s, 1H), 8.21 (d, 2H), 8.03 (d, 2H).

Preparation II1 5-(3-Oxo-propyl)-1H-pyrazole-3-carboxylic acid ethylester

[1772] Step A

[1773] 5-(tert-Butyl-dimethyl-silanyloxy)-pentan-2-one. A solution of3-acetyl-1-propanol (3.000 g, 29.37 mmol), tert-butyldimethylsilylchloride (4.522 g, 30.00 mmol), and imidazole (5.004 g, 73.5 mmol) inDMF (40 mL) was heated at 40° C. for 5 h and was stirred at roomtemperature for 66 h. Water (60 mL) was added and the product wasextracted into EtOAc (4×50 mL). The combined organic extracts werewashed with water (2×50 mL), dried over MgSO₄, filtered, andconcentrated. Purification by flash chromatography (hexanes:EtOAc 9:1)provided the title compound (3.722 g). ¹H NMR (400 MHz, CDCl₃) δ 3.59(t, 2H), 2.49 (t, 2H), 2.13 (s, 3H), 1.76 (m, 2H), 0.86 (s, 9H), 0.02(s, 6H); MS 217 (M+1).

[1774] Step B

[1775] 7-(tert-Butyl-dimethyl-silanyloxy)-2,4-dioxo-heptanoic acid ethylester. Diethyl oxalate (4.048 g, 37.7 mmol) was added to solid sodiumethoxide (0.472 g, 69.3 mmol) at 0° C. followed by slow addition of5-(tert-butyl-dimethyl-silanyloxy)-pentan-2-one (1.500 g, 69.3 mmol).The resulting orange solution was stirred at 0° C. for 10 minutes and atroom temperature for 3 h. Purification by flash chromatography (19:1hexanes:EtOAc to 9:1 EtOAc:MeOH) provided the title compound (1.982 g);MS 317 (M+1).

[1776] Step C

[1777]5-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-1H-pyrazole-3-carboxylicacid ethyl ester.

[1778] A solution of7-(tert-butyl-dimethyl-silanyloxy)-2,4-dioxo-heptanoic acid ethyl ester(1.627 g, 51.4 mmol) and hydrazine (17 mL, 55 mmol) in EtOH was heatedat reflux for 6 h. The reaction was concentrated in vacuo. Purificationby flash chromatography (6:4 hexanes:EtOAc) provided the title compound(333 mg). ¹H NMR (400 MHz, CDCl₃) δ 6.64 (s, 1H), 4.37 (q, 2H), 3.67 (t,2H), 2.85 (t, 2H), 1.88 (m, 2H), 1.38 (t, 3H), 0.88 (s, 9H), 0.05 (s,6H); MS 313 (M+1).

[1779] Step D

[1780] 5-(3-Hydroxy-propyl)-1H-pyrazole-3-carboxylic acid ethyl ester. Asolution of5-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-1H-pyrazole-3-carboxylicacid ethyl ester (327 mg, 1.05 mmol) and tetrabutylammonium fluoride(288 mg, 1.10 mmol) in THF (50 mL) was stirred at room temperature for 1h. The reaction mixture was concentrated in vacuo. Flash chromatography(EtOAc to EtOAc:MeOH 19:1) provided the title alcohol (165 mg). ¹H NMR(400 MHz, CDCl₃) δ 6.58 (s, 1H), 4.35 (q, 2H), 3.71 (t, 2H), 2.84 (t,2H), 1.91 (m, 2H), 1.36 (t, 3H); MS 199 (M+1).

[1781] Step E

[1782] 5-(3-Oxo-propyl)-1H-pyrazole-3-carboxylic acid ethyl ester.Dimethylsulfoxide (0.14 mL, 1.9 mmol) was slowly added to a solution ofoxalyl chloride (0.137 mg, 1.08 mmol) in CH₂Cl₂ (1 mL) and THF (1 mL) at−78° C. After stirring for 5 minutes, the solution was added dropwise toa solution of 5-(3-hydroxy-propyl)-1H-pyrazole-3-carboxylic acid ethylester (178 mg, 0.898 mmol) in THF (10 mL) at −78° C. The reaction wasstirred for 0.5 h and triethylamine (0.64 mL) was added. The suspensionwas stirred for 40 minutes and was warmed to room temperature. Thereaction was diluted with CH₂Cl₂:hexanes (1:4, 40 mL) and the mixturewas washed with 10% aqueous sodium bisulfate (15 mL) followed by water(2×10 mL). The organic solution was dried over MgSO₄, filtered, andconcentrated to provide the title aldehyde. ¹H NMR (400 MHz, CDCl₃) δ9.82 (s, 1H), 6.59 (s, 1H), 4.35 (q, 2H), 3.06 (m, 2H), 2.84 (t, 2H),1.91 (m, 2H), 1.34 (t, 3H); MS 197 (M+1).

Preparation JJ1 [5-(Methanesulfonylamino-methyl)-thiophen-2-yl]-aceticacid methyl ester

[1783] To a solution of thiophen-2-yl acetic acid methyl ester (2 mL,12.8 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (0.4 mL,4.8 mmol) dropwise over 10 minutes. Zinc chloride (78 mg, 0.57 mmol) wasadded and the reaction was lowered into a pre-heated water bath at 45°C. and was stirred for 15 minutes. HCl (g) was bubbled into the solutionfor 2-3 minutes. The temperature of the reaction rose to about 60° C.Upon cooling, 37% aqueous formaldehyde (1.24 mL, 16 mmol) was addeddropwise and the temperature rose to 70° C. The reaction was cooled toroom temperature and methanesulfonamide (1.25 g, 12.8 mmol) was added inportions. The reaction was stirred for 3 h and was poured into EtOAc (60mL). The organic solution was washed with water and the aqueous solutionwas washed with EtOAc (60 mL). The combined organic solutions werewashed with brine, dried over MgSO₄, filtered, and concentrated.Purification by flash chromatography (CHCl₃) provided the title compound(69%) as a gold oil. ¹H NMR (400 MHz, CDCl₃) δ 6.85 (d, 1H), 6.70 (d,1H), 5.20 (m, 1H), 4.40 (s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 2.80 (s,3H).

Preparation KK1 5-(3-Bromo-propyl)-benzo[1,3]dioxole

[1784] Step A

[1785] 3-Benzo[1,3]dioxol-5-yl-propan-1-ol. Lithium aluminum hydride (1Min THF, 30 mL, 30 mmol) was added slowly to a solution of3-benzo[1,3]dioxol-5-yl-propionic acid (5.83 g, 30 mmol) in THF (60 mL)at 0° C. The reaction was warmed to room temperature and was stirred for2 h. The solution was added in portions to a mixture of ice (200 g) andconcentrated HCl (2 mL). The product was extracted into EtOAc. Theorganic solution was dried over MgSO₄, filtered, and concentrated.Purification by flash chromatography (hexanes:EtOAc 6:4) provided thetitle alcohol (4.51 g). ¹H NMR (400 MHz, CDCl₃) δ 6.73-6.62 (m, 3H),5.91 (s, 2H), 3.66 (t, 2H), 2.63 (t, 2H), 1.84 (m, 2H).

[1786] Step B

[1787] 5-(3-Bromo-propyl)-benzo[1,3]dioxole. Following the proceduredescribed in Step B of Preparation O1,3-benzo[1,3]dioxol-5-yl-propan-1-ol was converted to the title bromide.¹H NMR (400 MHz, CDCl₃) δ 6.74-6.63 (m, 3H), 5.92 (s, 2H), 3.37 (t, 2H),2.69 (t, 2H), 2.11 (m, 2H).

PreparationLL1 2-(3-Iodo-propyl)-furan

[1788] To a solution of 3-furan-2-yl-propan-1-ol (6.3 g, 50 mmol) inpyridine (40 mL) at −15° C. was added p-toluenesulfonyl chloride (11.4g, 60 mmol) in portions and the reaction was stirred for 3 h. Water(10×0.5 mL) was added and the mixture was poured into a mixture ofconcentrated HCl (65 mL) and ice (200 gm). The product was extractedinto Et₂O and the organic solution was dried over MgSO₄, filtered, andconcentrated to provide a yellow oil. The oil was added to a mixture ofNal (9 g, 60 mmol) in acetone (70 mL) and the reaction was stirred for15 h. The insolubles were removed by filtration and the filtrate wasconcentrated in vacuo. Purification by flash chromatography (hexanes)provided the title compound (7.2 g). ¹H NMR (400 MHz, CDCl₃) δ 7.30 (m,1H), 6.28 (m, 1H), 6.04 (m, 1H), 3.19 (t, 2H), 2.75 (t, 2H), 2.14 (m,2H).

Preparation MM1 3-(3-Amino-propyl)-benzoic acid methyl esterhydrochloride salt

[1789] Step A

[1790] 3-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-benzoic acid methylester. Following the general procedure described in Step A ofPreparation C1, prop-2-ynyl-carbamic acid tert-butyl ester was coupledto 3-bromomethylbenzoate to provide the title compound. MS 307 (M+18).

[1791] Step B

[1792] 3-(3-tert-Butoxycarbonylamino-propyl)-benzoic acid methyl ester.Following the general procedure described in Step B of Preparation C1,3-(3-tert-butoxycarbonylamino-prop-1-ynyl)-benzoic acid methyl ester washydrogenated to provide the title compound. MS 311 (M+18).

[1793] Step C

[1794] 3-(3-Amino-propyl)-benzoic acid methyl ester hydrochloride salt.A solution of 3-(3-tert-butoxycarbonylamino-propyl)-benzoic acid methylester (565 mg) in MeOH (25 mL) was cooled to 0° C. and the solution wassaturated with HCl (g). The reaction was stirred at room temperature for1.5 h and was concentrated in vacuo to provide the title amine (399 mg).MS 194 (M+1).

Preparation NN1 [3-(2-Methanesulfonylamino-ethyl)-phenyl]-acetic acidtert-butyl ester

[1795] Step A

[1796] 3-Bromo-phenyl acetic acid tert-butyl ester. A mixture of3-bromo-phenyl acetic acid (5.00 g, 23.24 mmol), tert-butanol (1.89 g,25.57 mmol), DMAP (3.12 g, 25.57 mmol), and DCC (5.27 g, 25.57 mmol) inCH₂Cl₂ (150 mL) was stirred for 24 h at room temperature. The reactionwas filtered and the filtrate was concentrated in vacuo. The residue wasdissolved in EtOAc and the mixture was filtered. The organic solutionwas washed consecutively with 5.5% HCl, water, saturated NaHCO₃, andbrine. The organic solution was dried over MgSO₄, filtered, andconcentrated to provide the title compound (5.64 g).

[1797] Step B

[1798] {2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-aceticacid tert-butyl ester. A mixture of 3-bromo-phenyl acetic acidtert-butyl ester (5.64 g, 20.80 mmol), N-vinyl phthalimide (3.60 g,20.80 mmol), diisopropylethylamine (3.63 g, 28.08 mmol), palladiumacetate (107 mg, 0.478 mmol), and tri-o-tolylphosphine (475 mg, 1.56mmol) in acetonitrile (10 mL) was stirred at 90° C. for 20 h. Thereaction was cooled to room temperature and ice water (50 mL) was added.EtOAc (50 mL) was added and the organic solution was washed with 5.5%HCl followed by brine. The organic solution was dried over MgSO₄,filtered, and concentrated. Purification by flash chromatography(hexanes:EtOAc 9:1 to 4:1) provided the title compound (1.95 g). MS 381(M+18).

[1799] Step C

[1800] {2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-phenyl}-aceticacid tert-butyl ester.

[1801] To a solution of{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-acetic acidtert-butyl ester (1.95 g) in THF (50 mL) was added 10% Pd on carbon(1.00 g) and the reaction was hydrogenated on a Parr shaker at 50 psifor 24 h. The catalyst was removed by filtration through Celite with theaid of THF. The volatiles were removed in vacuo to provide the titlecompound (1.97 g). MS 383 (M+18).

[1802] Step D

[1803] [2-(2-Amino-ethyl)-phenyl]-acetic acid tert-butyl ester. Asolution of{2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-acetic acidtert-butyl ester (1.97 g) and hydrazine hydrate (1.97 mL) in EtOH (75mL) was heated at reflux for 90 minutes. The solids were removed byfiltration and the filtrate was concentrated in vacuo. The residue wasdissolved in EtOAc (50 mL) and the solution was washed with saturatedNaHCO₃ followed by brine. The organic solution was dried over MgSO₄,filtered, and concentrated. Purification by flash chromatography(CHCl₃:MeOH 97.5:2.5 to 95:5 to 9:1) provided the title amine (853 mg).MS 236 (M+1).

[1804] Step E

[1805] [3-(2-Methanesulfonylamino-ethyl)-phenyl]-acetic acid tert-butylester. A mixture of [2-(2-amino-ethyl)-phenyl]-acetic acid tert-butylester (422.5 mg, 1.795 mmol), triethylamine (908 mg, 8.977 mmol), andmethanesulfonyl chloride (226.2 mg, 1.975 mmol) in CH₂Cl₂ (20 mL) wascombined and stirred at 0° C. for 18 h. The organic solution was washedconsecutively with dilute HCl, water, saturated NaHCO₃, and brine. Theorganic solution was dried over MgSO₄, filtered, and concentrated toprovide the title sulfonamide (535 mg). MS 331 (M+18).

Preparation OO1 5-(3-Methanesulfonylamino-propyl)-furan-2-carboxylicacid methyl ester

[1806] To a solution of 5-(3-amino-propyl)-furan-2-carboxylic acidmethyl ester hydrochloride salt (see Preparation DD2) (150 mg, 0.683mmol), and triethylamine (0.313 mL, 2.25 mmol) in CH₂Cl₂ (15 mL) at 0°C. was added methanesulfonyl chloride (86 mg, 0.75 mmol). The reactionwas stirred at room temperature for 18 h. The organic solution waswashed consecutively with dilute HCl, water, saturated NaHCO₃, andbrine. The organic solution was dried over MgSO₄, filtered, andconcentrated to provide the title sulfonamide (156 mg). MS 262 (M+1).

Preparation PP1 5-(3-Amino-propyl)-tetrahydrofuran-2-carboxylic acidmethyl ester hydrochloride salt

[1807] Step A

[1808] 5-(3-tert-Butoxycarbonylamino-prop-1-ynyl)-furan-2-carboxylicacid methyl ester.

[1809] The title compound was prepared using the method described inStep A of Preparation DD1.

[1810] Step B

[1811]5-(3-tert-Butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acidmethyl ester and5-(3-tert-Butoxycarbonylamino-propyl)-furan-2-carboxylic acid methylester. To a solution of5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-furan-2-carboxylic acidmethyl ester (1.69 g) in MeOH (50 mL) was added 10% palladium on carbon(850 mg) and the mixture was hydrogenated on a Parr shaker at 50 psi for18 h. The catalyst was removed via filtration through Celite and thevolatiles were concentrated in vacuo. Flash chromatography(hexanes:EtOAc 4:1) provided5-(3-tert-butoxycarbonylamino-propyl)-furan-2-carboxylic acid methylester (422 mg, MS 284 M+) followed by5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acidmethyl ester (903 mg).

[1812] Step C

[1813] 5-(3-Amino-propyl)-tetrahydrofuran-2-carboxylic acid methyl esterhydrochloride salt.

[1814] The title compound was prepared from5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acidmethyl ester following the procedure described in Step C for PreparationDD2.

Preparation QQ1 3-(1H-Indol-3-yl)-propylamine

[1815] The title reagent can be prepared using the method described byJackson in J. Am. Chem. Soc., 52, 5029-5033, 1930.

Preparaton RR1 2-(Biphenyl-2-yloxy)-ethylamine

[1816] The title reagent can be prepared using the method described inGB 521575.

Preparation SS1 2-(3-Chloro-phenylsulfanyl)-ethylamine

[1817] The title reagent can be prepared using the method described inFed. Rep. Ger. Sci.

[1818] Pharm., 56, 4, 229-234, 1988.

Preparation TT1 2-(4-Chloro-phenylsulfanyl)-ethylamine

[1819] The title reagent can be prepared using the method described inCan. J. Chem., 37, 325-329, 1959.

Preparation UU1 3-(4-Chloro-phenyl)-propylamine

[1820] The title reagent can be prepared using the method described inJ. Med. Chem., 39, 25, 4942-4951, 1996.

Preparation VV1 4-Phenethylsulfanyl-benzaldehyde

[1821] The title reagent can be prepared using the method described inEP 332331.

Preparation WW1 4-(2-Oxo-pyrrolidin-1-yl)-benzaldehyde

[1822] The title compound can be prepared using the method described byKukalenko in Chem. Heterocycl. Compd. (Engl. Transl.), 8, 43, 1972.

Preparation XX1 4-Cyclohexyl-benzylamine

[1823] The title compound can be prepared using the method described byMeglio and coworkers in Farmaco Ed. Sci.; IT; 35, 3, 191-202, 1980.

Preparation YY1 3-Hydroxy-4-propoxy-benzaldehyde

[1824] The title compound can be prepared using the method described byBeke in Acta Chim. Acad. Sci. Hung., 14, 325-8, 1958.

Preparation ZZ1 5-Phenyl-furan-2-carbaldehyde

[1825] The title compound can be prepared using the method described byD'Auria and coworkers in Heterocycles, 24, 6, 1575-1578, 1986.

1. A compound having the Formula I

or a pharmaceutically acceptable salt or prodrug thereof wherein either(i): B is N; A is (C₁-C₆)alkylsulfonyl, (C₃-C₇)cycloalkylsulfonyl,(C₃-C₇)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di- or tri-substituted on carbon independently with hydroxy,(C₁-C₄)alkyl or halo; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₁-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,—(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; W is oxy, thio, sulfino,sulfonyl, aminosulfonyl-, -mono-N—(C₁-C₄)alkyleneaminosulfonyl-,sulfonylamino, N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines; X is afive or six membered aromatic ring optionally having one or twoheteroatoms selected independently from oxygen, nitrogen, and sulfur;said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl; Z is carboxyl,(C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl orphenylsulfonylcarbamoyl; K is a bond, (C₁-C₈)alkylene,thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with fluoro, methyl or chloro; M is —Ar,—Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar² wherein Ar, Ar¹ and Ar² are eachindependently a partially saturated, fully saturated or fullyunsaturated five to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated five or six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen; said Ar, Ar¹ and Ar²moieties optionally substituted, on one ring if the moiety ismonocyclic, or one or both rings if the moiety is bicyclic, on carbonwith up to three substituents independently selected from R¹, R² and R³wherein R¹, R² and R³ are hydroxy, nitro, halo, (C₁-C₆)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl; R¹, R² and R³ are optionally mono-,di- or tri-substituted on carbon independently with halo or hydroxy; andV is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro with the proviso that when K is(C₂-C₄)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl,cyclohept-1-yl or cyclooct-1-yl then said (C₅-C₈)cycloalkyl substituentsare not substituted at the one position with hydroxy; or (ii): B is N; Ais (C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said A moietiesoptionally mono-, di- or tri-substituted independently on carbon withhydroxy or halo; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,—(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; W is oxy, thio, sulfino,sulfonyl, aminosulfonyl-, -mono-N—(C₁-C₄)alkyleneaminosulfonyl-,sulfonylamino, N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines; X is afive or six membered aromatic ring optionally having one or twoheteroatoms selected independently from oxygen, nitrogen, and sulfur;said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl; Z is carboxyl,(C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl orphenylsulfonylcarbamoyl; K is (C₁-C₈)alkylene, thio(C₁-C₄)alkylene oroxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionally mono-unsaturated andwherein K is optionally mono-, di- or tri-substituted independently withfluoro, methyl or chloro; M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar²wherein Ar, Ar¹ and Ar² are each independently a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated five or sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon with up to three substituents independently selected from R¹, R²and R³ wherein R¹, R² and R³ are H, hydroxy, nitro, halo, (C₁-C₆)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl; R¹, R² and R³ are optionally mono-,di- or tri-substituted independently on carbon with halo or hydroxy; andV is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro with the proviso that when K is(C₂-C₄)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl,cyclohept-1-yl or cycloct-1-yl then said (C₅-C₈)cycloalkyl substituentsare not substituted at the one position with hydroxy and with theproviso that 6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoicacid and its ethyl ester are not included or (iii): B is C(H); A is(C₁-C₆)alkanoyl, or (C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said A moietiesoptionally mono-, di- or tri-substituted on carbon independently withhydroxy or halo; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₁-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,—(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; W is oxy, thio, sulfino,sulfonyl, aminosulfonyl-, -mono-N—(C₁-C₄)alkyleneaminosulfonyl-,sulfonylamino, N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines; X is afive or six membered aromatic ring optionally having one or twoheteroatoms selected independently from oxygen, nitrogen and sulfur;said ring optionally mono-, or di-substituted independently with halo,(C₁-C₃)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy,hydroxyl, (C₁-C₄)alkoxy, or carbamoyl; Z is carboxyl,(C₁-C₆)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl,5-oxo-1,2,4-oxadiazolyl, (C₁-C₄)alkylsulfonylcarbamoyl orphenylsulfonylcarbamoyl; K is a bond, (C₁-C₈)alkylene,thio(C₁-C₄)alkylene, (C₄-C₇)cycloalkyl(C₁-C₆)alkylene oroxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionally mono-unsaturated andwherein K is optionally mono-, di- or tri-substituted independently withfluoro, methyl or chloro; M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar² or —Ar¹—O—Ar²wherein Ar, Ar¹ and Ar² are each independently a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated five or sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon with up to three substituents independently selected from R¹, R²and R³ wherein R¹, R² and R³ are H, hydroxy, nitro, halo, (C₁-C₆)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl, (C₁-C₈)alkanoyl,(C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl; R¹, R² and R³ are optionally mono-,di- or tri-substituted on carbon independently with halo or hydroxy; andV is a bond or (C₁-C₃)alkylene optionally mono- or di-substitutedindependently with hydroxy or fluoro with the proviso that when K is(C₂-C₄)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl,cyclohept-1-yl or cyclooct-1-yl then said (C₅-C₈)cycloalkyl substituentsare not substituted at the one position with hydroxy.
 2. A compound asrecited in claim 1 wherein B is N; A is (C₁-C₆)alkylsulfonyl,(C₃-C₆)cycloalkylsulfonyl or (C₃-C₆)cycloalkyl(C₁-C₆)alkylsulfonyl, saidA moieties optionally mono-, di-, or tri-substituted on carbon withfluoro; X is phenyl, thienyl, or thiazolyl said phenyl, thienyl orthiazolyl optionally mono- or di-substituted independently with fluoro,chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; Wis oxy, thio or sulfonyl; Z is carboxyl, (C₁-C₄)alkoxycarbonyl ortetrazolyl; K is methylene or ethylene; Ar, Ar¹ and Ar² are eachindependently (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl; R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-,di- or tri-substituted independently with hydroxy, fluoro or chloro; andR² and R³ are chloro, fluoro, methyl, methoxy, difluoromethoxy,trifluoromethoxy or trifluoromethyl.
 3. A compound as recited in claim 2wherein A is (C₁-C₃)alkylsulfonyl; Q is—(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-, —(C₄-C₈)alkylene-, said—(C₄-C₈)alkylene- optionally substituted with up to four substituentsindependently selected from fluoro or (C₁-C₄)alkyl, —X—(C₂-C₅)alkylene-,—(C₁-C₅)alkylene-X—, —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar¹—V—Ar² or —Ar¹—O—Ar²wherein Ar¹ and Ar² are each independently phenyl, pyridyl or thienyl; Vis a bond or (C₁-C₂)alkylene; R¹ is chloro, fluoro, (C₁-C₄)alkyl or(C₁-C₄)alkoxy, said (C₁-C₄)alkyl and (C₁-C₄)alkoxy optionally mono-, di-or tri-substituted independently with hydroxy or fluoro; and R² and R³are each independently chloro or fluoro.
 4. A compound as recited inclaim 3 wherein the compound is7-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid,7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoicacid, or7-[(2′-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoicacid.
 5. A compound as recited in claim 3 wherein A is methylsulfonyl; Qis n-hexylene; Z is carboxyl; K is methylene; and M is4-(2-hydroxymethylphenyl)phenyl.
 6. A compound as recited in claim 3wherein A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K ismethylene; and M is 4-(3-hydroxymethylthien-2-yl)phenyl.
 7. A compoundas recited in claim 3 wherein A is methylsulfonyl; Q is n-hexylene; Z iscarboxyl; K is methylene; and M is 4-(2-chlorophenyl)phenyl.
 8. Acompound as recited in claim 1 wherein B is N; A is(C₁-C₆)alkylsulfonyl, (C₃-C₆)cycloalkylsulfonyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkylsulfonyl; X is phenyl, thienyl, orthiazolyl said phenyl, thienyl or thiazolyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl,methoxy, difluoromethoxy or trifluoromethyloxy; W is oxy, thio orsulfonyl; Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl; K is(C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkylene optionallymono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with methyl, fluoro or chloro; M is —Ar,said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl,naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl,benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl,benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl,cyclopentyl, cyclobutyl, cycloheptyl or chromanyl; R¹ is halo,(C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,optionally mono-, di- or tri-substituted independently with hydroxy,fluoro or chloro; and R² and R³ are each independently hydroxy, halo,trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy, (C₁-C₅)alkanoyl, cyano,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl,difluoromethoxy, trifluoromethoxy or carbamoyl.
 9. A compound as recitedin claim 8 wherein K is methylene; A is (C₁-C₃)alkylsulfonyl; M is —Arand —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl,cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R¹;R¹ is (C₁-C₇)alkyl or (C₁-C₅)alkoxy, said (C₁-C₇)alkyl or (C₁-C₅)alkoxyoptionally mono-, di- or tri-substituted independently with hydroxy orfluoro; and R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.
 10. A compound asrecited in claim 9 wherein the compound is7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoic acid,7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid,7-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoicacid or(3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid.
 11. A compound as recited in claim 9 wherein Q is—(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and W is oxy.
 12. A compound asrecited in claim 9 wherein Q is —(C₃-C₈)alkylene-, said—(C₃-C₈)alkylene- optionally substituted with from one to fourfluorines.
 13. A compound as recited in claim 12 wherein A ismethylsulfonyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is4-(1-hydroxy-n-hexylene-1-yl)phenyl.
 14. A compound as recited in claim12 wherein A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K ismethylene; and M is 4-(n-butylene-1-yl)phenyl.
 15. A compound as recitedin claim 12 wherein A is methylsulfonyl; Q is n-hexylene; Z is carboxyl;K is methylene; and M is 5-(1-hydroxy-n-hexylene-1-yl)thien-2-yl.
 16. Acompound as recited in claim 9 wherein Q is —X—(C₁-C₅)alkylene-; and Xis thienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.
 17. A compound as recited in claim 9 wherein Q is—(C₁-C₅)alkylene-X—; and X is thienyl or phenyl; said phenyl and thienyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl or methoxy.
 18. A compound as recited in claim 9 whereinQ is —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and X is thienyl or phenyl;said phenyl and thienyl optionally mono- or di-substituted independentlywith fluoro, chloro, trifluoromethyl or methoxy.
 19. A compound asrecited in claim 18 wherein A is methylsulfonyl; Q is3-methylenephenylmethyl; Z is carboxyl; K is methylene; and M is4-(n-butylene-1-yl)phenyl.
 20. A compound as recited in claim 9 whereinQ is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-; X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 21. A compoundas recited in claim 9 wherein Q is—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 22. A compoundas recited in claim 9 wherein Q is—(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-; W is oxy; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 23. Acompound as recited in claim 9 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar isphenyl, thiazolyl, pyridyl or thienyl.
 24. A compound as recited inclaim 9 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.
 25. A compound as recited in claim 9 wherein Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-; W isoxy; and X is thienyl or phenyl; said phenyl and thienyl optionallymono- or di-substituted independently with fluoro, chloro,trifluoromethyl or methoxy.
 26. A compound as recited in claim 9 whereinQ is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.
 27. A compound asrecited in claim 9 wherein Q is—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 28. Acompound as recited in claim 8 wherein A is (C₁-C₃)alkylsulfonyl; K is(C₁-C₈)alkylene; —Ar is phenyl, thiazolyl, pyridyl, thienyl,benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxine,2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentylor cyclohexyl; and R¹, R² and R³ are each independently hydroxy, halo,trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or(C₁-C₇)alkyl.
 29. A compound as recited in claim 28 wherein the compoundis 7-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid,7-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid or5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid.
 30. A compound as recited in claim 28 wherein Q is—(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and W is oxy.
 31. A compound asrecited in claim 28 wherein Q is —(C₃-C₈)alkylene-, said—(C₃-C₈)alkylene- optionally substituted with from one to fourfluorines.
 32. A compound as recited in claim 31 wherein A ismethylsulfonyl; Q is n-hexylene; Z is carboxyl; K is propylene; and M is3-chlorophenyl.
 33. A compound as recited in claim 31 wherein A ismethylsulfonyl; Q is n-hexylene; Z is carboxyl; K is propylene; and M is3,5-dichlorophenyl.
 34. A compound as recited in claim 28 wherein Q is—X—(C₁-C₅)alkylene-; and X is thienyl or phenyl; said phenyl and thienyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl or methoxy.
 35. A compound as recited in claim 28wherein Q is —(C₁-C₅)alkylene-X—; and X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy.
 36. A compound as recited inclaim 35 wherein A is methylsulfonyl; Q—Z is3-(2-carboxylthien-5-yl)-n-propylene K is propylene; and M is3-chlorophenyl.
 37. A compound as recited in claim 28 wherein Q is—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy.
 38. A compound as recited inclaim 28 wherein Q is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-; X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and W is oxy.
 39. A compound as recited in claim 28 wherein Qis —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 40. A compoundas recited in claim 28 wherein Q is—(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-; W is oxy; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 41. Acompound as recited in claim 28 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar isphenyl, thiazolyl, pyridyl or thienyl;
 42. A compound as recited inclaim 28 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.
 43. A compound as recited in claim 28 wherein Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-; W isoxy; and X is thienyl or phenyl; said phenyl and thienyl optionallymono- or di-substituted independently with fluoro, chloro,trifluoromethyl or methoxy.
 44. A compound as recited in claim 28wherein Q is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.
 45. Acompound as recited in claim 28 wherein Q is—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 46. Acompound as recited in claim 8 wherein A is (C₁-C₃)alkylsulfonyl; K isoxy(C₁-C₄)alkylene; —Ar is phenyl, thienyl, thiazolyl, pyridyl,benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and R¹, R² and R³ areeach independently hydroxy, halo, trifluoromethyl, difluoromethoxy,trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 47. A compound asrecited in claim 46 wherein the compound is7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid,5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid or N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.
 48. A compound as recited inclaim 46 wherein Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and W is oxy.49. A compound as recited in claim 46 wherein Q is —(C₃-C₈)alkylene-,said —(C₃-C₈)alkylene- optionally substituted with from one to fourfluorines.
 50. A compound as recited in claim 49 wherein A ismethylsulfonyl; Q is n-hexylene; Z is carboxyl; K is oxyethylene; and Mis 3,5-dichlorophenyl.
 51. A compound as recited in claim 46 wherein Qis —X—(C₁-C₅)alkylene-; and X is thienyl or phenyl; said phenyl andthienyl optionally mono- or di-substituted independently with fluoro,chloro, trifluoromethyl or methoxy.
 52. A compound as recited in claim46 wherein Q is —(C₁-C₅)alkylene-X—; and X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy.
 53. A compound as recited inclaim 52 wherein A is methylsulfonyl; Q—Z is3-(2-carboxylthien-5-yl)-n-propylene; K is oxyethylene; and M is3,5-dichlorophenyl.
 54. A compound as recited in claim 46 wherein Q is—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy.
 55. A compound as recited inclaim 46 wherein Q is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-; X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and W is oxy.
 56. A compound as recited in claim 46 wherein Qis —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 57. A compoundas recited in claim 46 wherein Q is—(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-; W is oxy; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 58. Acompound as recited in claim 46 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar isphenyl, thiazolyl, pyridyl or thienyl.
 59. A compound as recited inclaim 46 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.
 60. A compound as recited in claim 46 wherein Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-; W isoxy; and X is thienyl or phenyl; said phenyl and thienyl optionallymono- or di-substituted independently with fluoro, chloro,trifluoromethyl or methoxy.
 61. A compound as recited in claim 46wherein Q is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.
 62. Acompound as recited in claim 46 wherein Q is—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 63. Acompound as recited in claim 8 wherein A is (C₁-C₃)alkylsulfonyl; K is(C₃-C₈)alkylene, said (C₃-C₈)alkylene being mono-unsaturated; —Ar isphenyl, thienyl, thiazolyl, pyridyl, cyclopentyl or cyclohexyl; and R¹,R² and R³ are each independently hydroxy, halo, trifluoromethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 64. Acompound as recited in claim 63 wherein the compound isTrans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-aceticacid,Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazolyl-5-yl)-hexyl]-methanesulfonamide,Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylicacid orTrans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-aceticacid.
 65. A compound as recited in claim 63 wherein Q is—(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-; and W is oxy.
 66. A compound asrecited in claim 65 wherein A is methylsulfonyl; Q ismethyloxy-n-butylene; Z is carboxyl; K is trans-2-n-propenylene; and Mis 3,5-dichlorophenyl.
 67. A compound as recited in claim 63 wherein Qis —(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionally substituted withfrom one to four fluorines.
 68. A compound as recited in claim 67wherein A is methylsulfonyl; Q is n-hexylene; Z is 5-(1H-tetrazolyl); Kis trans-2-n-propeneylene; and M is 3,5-dichlorophenyl.
 69. A compoundas recited in claim 63 wherein Q is —X—(C₁-C₅)alkylene-; and X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.
 70. A compound as recited in claim 63 wherein Q is—(C₁-C₅)alkylene-X—; and X is thienyl or phenyl; said phenyl and thienyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl or methoxy.
 71. A compound as recited in claim 70wherein A is methylsulfonyl; Q—Z is3-(2-carboxylthien-5-yl)-n-propylene; K is trans-2-n-propeneylene; and Mis 3,5-dichlorophenyl.
 72. A compound as recited in claim 63 wherein Qis —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-; and X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy.
 73. A compound as recited inclaim 63 wherein Q is —(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-; X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy; and W is oxy.
 74. A compound as recited in claim 63 wherein Qis —(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; X is thienyl or phenyl; saidphenyl and thienyl optionally mono- or di-substituted independently withfluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
 75. A compoundas recited in claim 63 wherein Q is—(C₂-C₄)alkylene-W—X—W—(C₁-C₃)alkylene-; W is oxy; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 76. Acompound as recited in claim 63 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-; and M is —Ar and —Ar isphenyl, thiazolyl, pyridyl or thienyl.
 77. A compound as recited inclaim 63 wherein Q is—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₃)alkylene-; and X isthienyl or phenyl; said phenyl and thienyl optionally mono- ordi-substituted independently with fluoro, chloro, trifluoromethyl ormethoxy.
 78. A compound as recited in claim 63 wherein Q is—(C₁-C₃)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-; W isoxy; and X is thienyl or phenyl; said phenyl and thienyl optionallymono- or di-substituted independently with fluoro, chloro,trifluoromethyl or methoxy.
 79. A compound as recited in claim 63wherein Q is —(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-.
 80. Acompound as recited in claim 63 wherein Q is—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; and X is thienyl orphenyl; said phenyl and thienyl optionally mono- or di-substitutedindependently with fluoro, chloro, trifluoromethyl or methoxy.
 81. Acompound as recited in claim 1 wherein B is N; A is (C₁-C₆)alkanoyl, or(C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said A moieties optionally mono-, di-or tri-substituted on carbon independently with hydroxy or halo; X isphenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; W is oxy,thio or sulfonyl; Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl; Kis (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with methyl, fluoro or chloro; Ar is(C₅-C₇)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl,isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl,furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl,benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl,cyclohexyl, cyclopentyl, or chromanyl; Ar¹ and Ar² are eachindependently (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl; R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and R² and R³ are eachindependently hydroxy, halo, difluoromethoxy, trifluoromethoxy,trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy, (C₁-C₅)alkanoyl, cyano,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl or carbamoyl.82. A compound as recited in claim 81 wherein A is (C₁-C₆)alkanoyl, said(C₁-C₆)alkanoyl optionally mono-, di- or tri-substituted on carbonindependently with halo; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; K is methylene or ethylene; M is—Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are each independentlyphenyl, pyridyl or thienyl; V is a bond or (C₁-C₂)alkylene; R¹ ischloro, fluoro, (C₁-C₄)alkyl or (C₁-C₆)alkoxy, said (C₁-C₄)alkyl and(C₁-C₆)alkoxy optionally mono-, di-or tri-substituted independently withhydroxy or fluoro; and R² and R³ are each independently chloro orfluoro.
 83. A compound as recited in claim 81 wherein A is(C₁-C₆)alkanoyl said (C₁-C₆)alkanoyl optionally mono-, di- ortri-substituted independently on carbon with hydroxy or halo; K ismethylene; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-, —(C₄-C₈)alkylene-,said —(C₄-C₈)alkylene- optionally substituted with up to foursubstituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-, M is —Ar and —Ar is phenyl,thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl orcyclohexyl wherein —Ar is substituted with at least R¹; R¹ is(C₁-C₇)alkyl or (C₁-C₅)alkoxy, said (C₁-C₇)alkyl or (C₁-C₅)alkoxyoptionally mono-, di- or tri-substituted independently with hydroxy orfluoro; and R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.
 84. A compound asrecited in claim 81 wherein A is (C₁-C₆)alkanoyl said (C₁-C₆)alkanoyloptionally mono-, di- or tri-substituted independently on carbon withhalo; K is (C₁-C₈)alkylene; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar and —Ar is phenyl,thienyl, benzofuranyl, benzo[1,3]dioxolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl,benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and R¹, R² and R³ areeach independently hydroxy, halo, trifluoromethyl, difluoromethoxy,trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 85. A compound asrecited in claim 81 wherein A is (C₁-C₆)alkanoyl said (C₁-C₆)alkanoyloptionally mono-, di- or tri-substituted on carbon independently withhalo; K is oxy(C₁-C₄)alkylene; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar and —Ar is phenyl,thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and R¹, R² andR³ are each independently hydroxy, halo, trifluoromethyl,difluoromethoxy, trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 86. Acompound as recited in claim 81 wherein A is (C₃-C₆)alkanoyl said(C₃-C₆)alkanoyl optionally mono-, di- or tri-substituted on carbonindependently with halo; K is (C₃-C₈)alkylene, said (C₃-C₈)alkylenebeing mono-unsaturated; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar and —Ar is phenyl,thienyl, cyclopentyl or cyclohexyl; and R¹, R² and R³ are eachindependently hydroxy, halo, trifluoromethyl, trifluoromethoxy,(C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 87. A compound as recited in claim 1wherein B is C(H); A is (C₁-C₆)alkanoyl, or(C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said A moieties optionally mono-, di-or tri-substituted independently on carbon with hydroxy or halo; X isphenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyloptionally mono- or di-substituted independently with fluoro, chloro,trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; W is oxy,thio or sulfonyl; Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl; Kis (C₁-C₈)alkylene or oxy(C₁-C₄)alkylene, said (C₁-C₈)alkyleneoptionally mono-unsaturated and wherein K is optionally mono-, di- ortri-substituted independently with hydroxy, fluoro or chloro; Ar is(C₅-C₇)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl,isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl,furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl,pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl,benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl,cyclohexyl, cyclopentyl, or chromanyl; Ar¹ and Ar² are eachindependently (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl; R¹ is halo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy,(C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, optionally mono-, di- or tri-substitutedindependently with hydroxy, fluoro or chloro; and R² and R³ are eachindependently hydroxy, halo, difluoromethoxy, trifluoromethoxy,trifluoromethyl, (C₁-C₇)alkyl, (C₁-C₄)alkoxy, (C₁-C₅)alkanoyl, cyano,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkyl, formyl or carbamoyl.88. A compound as recited in claim 87 wherein A is (C₁-C₆)alkanoyl, saidA optionally mono-, di- or tri-substituted on carbon independently withhalo; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-, —(C₄-C₈)alkylene-, said—(C₄-C₈)alkylene- optionally substituted with up to four substituentsindependently selected from fluoro or (C₁-C₄)alkyl, —X—(C₂-C₅)alkylene-,—(C₁-C₅)alkylene-X—, —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; K is methylene or ethylene; M is—Ar¹—V—Ar² or —Ar¹—O—Ar² wherein Ar¹ and Ar² are each independentlyphenyl, pyridyl or thienyl; V is a bond or (C₁-C₂)alkylene; R¹ ischloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said (C₁-C₄)alkyl and(C₁-C₄)alkoxy optionally mono-, di-or tri-substituted independently withhydroxy or fluoro; and R² and R³ are each independently chloro orfluoro.
 89. A compound as recited in claim 87 wherein A is(C₁-C₆)alkanoyl, said A optionally mono-, di- or tri-substituted oncarbon independently with hydroxy or halo; K is methylene; Q is—(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-, —(C₄-C₈)alkylene-, said—(C₄-C₈)alkylene- optionally substituted with up to four substituentsindependently selected from fluoro or (C₁-C₄)alkyl, —X—(C₂-C₅)alkylene-,—(C₁-C₅)alkylene-X—, —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar and —Ar is phenyl,thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl orcyclohexyl wherein —Ar is substituted with at least R¹; R¹ is(C₁-C₇)alkyl or (C₁-C₆)alkoxy, said (C₁-C₇)alkyl or (C₁-C₆)alkoxyoptionally mono-, di- or tri-substituted independently with hydroxy orfluoro; and R² and R³ are each independently chloro, fluoro, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.
 90. A compound asrecited in claim 87 wherein A is (C₁-C₆)alkanoyl, said A optionallymono-, di- or tri-substituted on carbon independently with halo; K is(C₁-C₈)alkylene; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar and —Ar is phenyl,thienyl, benzofuranyl, benzo[1,3]dioxolyl,2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl,benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and R¹, R² and R³ areeach independently hydroxy, halo, trifluoromethyl, trifluoromethoxy,(C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 91. A compound as recited in claim 87wherein A is (C₁-C₆)alkanoyl said A optionally mono-, di- ortri-substituted on carbon independently with halo; K isoxy(C₁-C₄)alkylene; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₄-C₈)alkylene-, said —(C₄-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar and —Ar is phenyl,thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and R¹, R² andR³ are each independently hydroxy, halo, trifluoromethyl,trifluoromethoxy, (C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 92. A compound asrecited in claim 87 wherein A is (C₁-C₆)alkanoyl, said A optionallymono-, di- or tri-substituted on carbon independently with halo; K is(C₃-C₈)alkylene, said (C₃-C₈)alkylene being mono-unsaturated; Q is—(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-, —(C₄-C₈)alkylene-, said—(C₄-C₈)alkylene- optionally substituted with up to four substituentsindependently selected from fluorines or (C₁-C₄)alkyl,—X—(C₂-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-, or—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-; M is —Ar and —Ar is phenyl,thienyl, cyclopentyl or cyclohexyl; and R¹, R² and R³ are eachindependently hydroxy, halo, trifluoromethyl, trifluoromethoxy,(C₁-C₄)alkoxy or (C₁-C₇)alkyl.
 93. A compound as recited in claim 83wherein A is propanoyl; Q is n-hexylene; Z is carboxyl; K is methylene;and M is 4-(n-1-hydroxylhexyl)phenyl.
 94. A compound as recited in claim49 wherein A is methylsulfonyl; Q is n-hexylene; Z is 5-(1H-tetrazolyl);K is oxyethyl; and M is 3,5-dichlorophenyl.
 95. A compound as recited inclaim 72 wherein A is methylsulfonyl; Q is 3-methylenephenylmethyl; Z iscarboxyl; K is trans-2-n-propenylene; and M is 3,5-dichlorophenyl.
 96. Amethod for treating a mammal having a condition which presents with lowbone mass comprising administering to said mammal a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt or prodrug thereof.
 97. The method as recited in claim96 wherein osteoporosis, osteotomy, childhood idiopathic bone loss orbone loss associated with periodontitis is treated.
 98. The method asrecited in claim 97 wherein osteoporosis is treated in a human.
 99. Themethod as recited in claim 96 wherein glucocorticoid-inducedosteoporosis, hyperthyroidism-induced osteoporosis,immobilization-induced osteoporosis, heparin-induced osteoporosis orimmunosuppressive-induced osteoporosis is treated.
 100. A method foraugmenting and maintaining bone mass in a mammal comprisingadministering to a mammal a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt or prodrugthereof.
 101. The method as recited in claim 100 wherein bone healingfollowing facial reconstruction, maxillary reconstruction or mandibularreconstruction is treated, vertebral synostosis is induced or long boneextension is enhanced, the healing rate of a bone graft is enhanced orprosthetic ingrowth is enhanced.
 102. The method as recited in claim 100wherein a bone fracture is treated in a human.
 103. A pharmaceuticalcomposition which comprises a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt or prodrugthereof and a pharmaceutically acceptable carrier.
 104. Thepharmaceutical composition as recited in claim 103 for the treatment ofosteoporosis wherein the therapeutically effective amount is anosteoporosis treating amount.
 105. A pharmaceutical composition for theaugmentation of bone mass which comprises a bone mass augmenting amountof a compound of claim 1 or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.
 106. Thepharmaceutical composition as recited in claim 105 for the treatment ofa bone fracture wherein a bone fracture treating amount of a compound ofclaim 1 or a pharmaceutically acceptable salt or prodrug thereof isused.
 107. A pharmaceutical composition for the treatment of a conditionwhich presents with low bone mass in a mammal which comprises a low bonemass condition treating amount of a compound of claim 1 or apharmaceutically acceptable salt or prodrug thereof and apharmaceutically acceptable carrier.
 108. A pharmaceutical compositioncomprising: a. a therapeutically effective amount of a compound of claim1 or a pharmaceutically acceptable salt or prodrug thereof; b. atherapeutically effective amount of an anti-resorptive agent; and c. apharmaceutical carrier.
 109. A pharmaceutical composition as recited inclaim 108 wherein the anti-resorptive agent is droloxifene, raloxifene,tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman,levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineor a pharmaceutically acceptable salt thereof.
 110. A pharmaceuticalcomposition as recited in claim 108 wherein the anti-resorptive agent istiludronic acid, alendronic acid, ibandronic acid, risedronic acid,etidronic acid, clodronic acid, and pamidronic acid or apharmaceutically acceptable salt thereof.
 111. A method for treating amammal having a condition which presents with low bone mass comprisingadministering to said mammal a. a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt or prodrugthereof; and b. a therapeutically effective amount of an anti-resorptiveagent.
 112. The method as recited in claim 111 wherein theanti-resorptive agent is droloxifene, raloxifene, tamoxifen,4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene,idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineor a pharmaceutically acceptable salt thereof.
 113. The method asrecited in claim 111 wherein the anti-resorptive agent is, tiludronicacid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid,clodronic acid, and pamidronic acid or a pharmaceutically acceptablesalt.
 114. A kit comprising: a. a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt or prodrugthereof and a pharmaceutically acceptable carrier in a first unit dosageform; b. a therapeutically effective amount of an anti-resorptive agentand a pharmaceutically acceptable carrier in a second unit dosage form;and c. container means for containing said first and second dosageforms.
 115. The kit as recited in claim 114 wherein the anti-resorptiveagent is droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen,toremifene, centchroman, levormeloxifene, idoxifene,6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol,{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone,Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;(−)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene;1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or1-(4′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineor a pharmaceutically acceptable salt thereof.
 116. The kit as recitedin 114 wherein the anti-resorptive agent is tiludronic acid, alendronicacid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid,and pamidronic acid or a pharmaceutically acceptable salt thereof. 117.A pharmaceutical composition comprising: a. a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable salt orprodrug thereof; b. a therapeutically effective amount of an anabolicagent other than a compound of claim 1 or a pharmaceutically acceptablesalt or prodrug thereof; and c. a pharmaceutical carrier.
 118. Thepharmaceutical composition as recited in claim 117 wherein the anabolicagent other than the claim 1 compound is IGF-1 optionally with IGF-1binding protein 3 prostaglandin, prostaglandin agonist/antagonist,sodium fluoride, parathyroid hormone (PTH), active fragments ofparathyroid hormone, growth hormone or growth hormone secretagogues or apharmaceutically acceptable salt thereof.
 119. A method for treating amammal which presents with low bone mass comprising administering tosaid a. a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt or prodrug thereof; and b. atherapeutically effective amount of a bone anabolic agent other than acompound of claim 1 or a pharmaceutically acceptable salt or prodrugthereof.
 120. The method as recited in claim 119 wherein the anabolicagent other than the claim 1 compound is IGF-1, prostaglandin,prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone(PTH), active fragments of parathyroid hormone, growth hormone or growthhormone secretagogues or a pharmaceutically acceptable salt thereof.121. A kit comprising: a. a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt or prodrugthereof and a pharmaceutically acceptable carrier in a first unit dosageform; b. a therapeutically effective amount of an anabolic agent otherthan a compound of claim 1 or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier in a secondunit dosage form; and c. container means for containing said first andsecond dosage forms.
 122. The kit as recited in claim 121 wherein theanabolic agent other than the claim 1 compound is IGF-1, prostaglandin,prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone(PTH), active fragments of parathyroid hormone, growth hormone or growthhormone secretagogues or a pharmaceutically acceptable salt thereof.123. A compound as recited in claim 1 wherein B is N; A is (C₁-C₃)alkylsulfonyl; Q is —(C₃-C₅)alkylene-O—(C₁-C₃)alkylene-,—(C₅-C₇)alkylene-, said —(C₅-C₇)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—(C₂-C₄)alkylene-X—, —(CH₂)-meta-phenylene-O—(CH₂)— optionally mono- ordi-substituted independently with methoxy, trifluoromethyl,difluoromethoxy, trifluoromethoxy, chloro or fluoro or—(CH₂)-meta-phenylene-(CH₂)— optionally mono- or di-substitutedindependently with methoxy, trifluoromethyl, difluoromethoxy,trifluoromethoxy, chloro or fluoro; M is —Ar¹—V—Ar² or —Ar¹—O—Ar²; V isa bond or —CH₂—; Z is carboxyl, (C₁-C₄)alkoxycarbonyl or tetrazolyl; Xis thienyl, thiazolyl, or furanyl; K is methylene; Ar¹ is phenyl,(C₅-C₇)cycloalkyl, furanyl, thienyl, thiazolyl, or pyridyl; Ar² is(C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl,oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl, triazolyl orpyrazolyl; R¹ is chloro, fluoro, (C₁-C₄)alkyl or (C₁-C₄)alkoxy, said(C₁-C₄)alkyl and (C₁-C₄)alkoxy optionally mono-, di- or tri-substitutedindependently with hydroxy or fluoro; and R² and R³ are eachindependently, methoxy, trifluoromethyl, difluoromethoxy,trifluoromethoxy, chloro or fluoro.
 124. A compound as recited in claim123 wherein Q is —(CH₂)-meta-phenylene-(CH₂)—, M is —Ar¹—Ar², Ar¹ isphenyl; Ar² is (C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl,pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl orpyrazolyl, said Ar² optionally mono- or di-substituted independentlywith R¹ or R²; R¹ is chloro, fluoro, methyl, methoxy, trifluoromethyl,difluoromethoxy or trifluoromethoxy; and R² is methoxy, chloro orfluoro.
 125. A compound as recited in claim 123 wherein Q is—(CH₂)-meta-phenylene-O—(CH₂)—, M is —Ar¹—Ar², Ar¹ is phenyl; Ar² is(C₅-C₇)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl,oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl, saidAr² optionally mono- or di-substituted independently with R¹ or R²; R¹is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy ortrifluoromethoxy; and R² is methoxy, chloro or fluoro.
 126. A compoundof claim 124 wherein A is methylsulfonyl; Z is carboxyl; and M is4-(cyclohexyl)phenyl.
 127. A compound of claim 124 wherein A ismethylsulfonyl; Z is carboxyl; and M is 4-(thiazol-2-yl)phenyl.
 128. Acompound of claim 124 wherein A is methylsulfonyl; Z is carboxyl; and Mis 4-(pyrazin-2-yl)phenyl.
 129. A compound as recited in claim 124wherein the compound is a.(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid; b.(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid; or c.(3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid.
 130. A compound as recited in claim 1 wherein B is N; A is(C₁-C₃)alkylsulfonyl; Q is —(C₂-C₄)alkylene-X—; X is thiazolyl orfuranyl; said thiazolyl or furanyl optionally mono- or di-substitutedindependently with methyl, methoxy, fluoro, chloro, trifluoromethyl,difluoromethoxy or trifluoromethoxy; K is oxy-ethylene or propylene,said propylene optionally being mono-unsaturated; M is —Ar, said —Ar isphenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, pyrimidyl,imidazolyl, cyclohexyl, cyclopentyl, cyclobutyl, or cycloheptyl; R¹ ishalo, (C₁-C₆)alkoxy, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkanoyl or(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, said (C₁-C₆)alkoxy, (C₁-C₇)alkyl,(C₃-C₇)cycloalkyl, C₁-C₇)alkanoyl or (C₃-C₇)cycloalkyl(C₁-C₄)alkyl,optionally mono-, di- or tri-substituted independently with hydroxy,fluoro or chloro; and R² and R³ are each independently methoxy,trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.131. A compound as recited in claim 130 wherein A is methylsulfonyl; Zis carboxyl, or (C₁-C₄)alkoxycarbonyl; Q is -propylene-X—; X isthiazolyl; K is oxy-ethylene or propylene; M is phenyl optionally mono-or di-substituted independently with fluoro, chloro, methoxy, methyl,difluoromethoxy, trifluoromethoxy or trifluoromethyl.
 132. A compound asrecited in claim 131 wherein Z is carboxyl; K is propylene; and M is3-(chloro)phenyl.
 133. A compound as recited in claim 131 wherein Z iscarboxyl; K is oxy-ethylene; and M is 3,5-dichlorophenyl.
 134. Acompound as recited in claim 130 wherein the compound is a.2-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid or b.2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylicacid.
 135. A compound having the Formula IA

or a pharmaceutically acceptable salt or prodrug thereof wherein either(i): B is N; A is (C₁-C₆)alkylsulfonyl, (C₃-C₇)cycloalkylsulfonyl,(C₃-C₇)cycloalkyl(C₁-C₆)alkylsulfonyl, said A moieties optionally mono-,di- or tri-substituted on carbon independently with hydroxy,(C₁-C₄)alkyl or halo; Q is —(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-,—(C₃-C₈)alkylene-, said —(C₃-C₈)alkylene- optionally substituted with upto four substituents independently selected from fluoro or (C₁-C₄)alkyl,—X—(C₁-C₅)alkylene-, —(C₁-C₅)alkylene-X—,—(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,—(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(C₀-C₅)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; W is oxy, thio, sulfino,sulfonyl, aminosulfonyl-, -mono-N—(C₁-C₄)alkyleneaminosulfonyl-,sulfonylamino, N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines; X istetrahydrofuranyl or a five or six membered aromatic ring optionallyhaving one or two heteroatoms selected independently from oxygen,nitrogen, and sulfur; said ring optionally mono-, or di-substitutedindependently with halo, (C₁-C₃)alkyl, trifluoromethyl,trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, orcarbamoyl; Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl,(C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl; K is a bond,(C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene, said(C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionallymono-, di- or tri-substituted independently with fluoro, methyl orchloro; M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar², —Ar¹—O—Ar²,—Ar¹—S—(C₁-C₃)—Ar²—, —Ar¹—(C₁-C₃)—S—Ar²— or —Ar¹—(C₁-C₃)—S—(C₁-C₃)—Ar²,wherein Ar, Ar¹ and Ar² are each independently a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated five or sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon, nitrogen or sulfur with up to three substituents independentlyselected from R¹, R² and R³ wherein R¹, R² and R³ are oxo, hydroxy,nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl,(C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl; (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl; R¹, R² and R³ are optionally mono-,di- or tri-substituted on carbon independently with halo or hydroxy; andV is a bond or (C₁-C₃)alkylene optionally mono-unsaturated andoptionally mono- or di-substituted independently with hydroxy or fluoro,with the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar iscyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said(C₅-C₈)cycloalkyl substituents are not substituted at the one positionwith hydroxy; or (ii): B is N; A is (C₁-C₆)alkanoyl, or(C₃-C₇)cycloalkyl(C₁-C₆)alkanoyl, said A moieties optionally mono-, di-or tri-substituted independently on carbon with hydroxy or halo; Q is—(C₂-C₆)alkylene-W—(C₁-C₃)alkylene-, —(C₄-C₈)alkylene-, said—(C₄-C₈)alkylene- optionally substituted with up to four substituentsindependently selected from fluoro or (C₁-C₄)alkyl, —X—(C₂-C₅)alkylene-,—(C₁-C₅)alkylene-X—, —(C₁-C₃)alkylene-X—(C₁-C₃)alkylene-,—(C₂-C₄)alkylene-W—X—(C₀-C₃)alkylene-,—(C₀-C₄)alkylene-X—W—(C₁-C₃)alkylene-,—(C₂-C₅)alkylene-W—X—W—(C₁-C₃)alkylene-, wherein the two occurrences ofW are independent of each other,—(C₁-C₄)alkylene-ethenylene-(C₁-C₄)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—(Co-C₅)alkylene-,—(C₁-C₄)alkylene-ethenylene-(C₀-C₂)alkylene-X—W—(C₁-C₃)alkylene-,—(C₁-C₄)alkylene-ethynylene-(C₁-C₄)alkylene-, or—(C₁-C₄)alkylene-ethynylene-X—(C₀-C₃)alkylene-; W is oxy, thio, sulfino,sulfonyl, aminosulfonyl-, -mono-N—(C₁-C₄)alkyleneaminosulfonyl-,sulfonylamino, N—(C₁-C₄)alkylenesulfonylamino, carboxamido,N—(C₁-C₄)alkylenecarboxamido, carboxamidooxy,N—(C₁-C₄)alkylenecarboxamidooxy, carbamoyl,-mono-N—(C₁-C₄)alkylenecarbamoyl, carbamoyloxy, or-mono-N—(C₁-C₄)alkylenecarbamoyloxy, wherein said W alkyl groups areoptionally substituted on carbon with one to three fluorines; X istetrahydrofuranyl or a five or six membered aromatic ring optionallyhaving one or two heteroatoms selected independently from oxygen,nitrogen, and sulfur; said ring optionally mono-, or di-substitutedindependently with halo, (C₁-C₃)alkyl, trifluoromethyl,trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C₁-C₄)alkoxy, orcarbamoyl; Z is carboxyl, (C₁-C₆)alkoxycarbonyl, tetrazolyl,1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl,(C₁-C₄)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl; K is(C₁-C₈)alkylene, thio(C₁-C₄)alkylene or oxy(C₁-C₄)alkylene, said(C₁-C₈)alkylene optionally mono-unsaturated and wherein K is optionallymono-, di- or tri-substituted independently with fluoro, methyl orchloro; M is —Ar, —Ar¹—V—Ar², —Ar¹—S—Ar², —Ar¹—O—Ar²,—Ar¹—S—(C₁-C₃)—Ar²—, —Ar¹—(C₁-C₃)—S—Ar²— or —Ar¹—(C₁-C₃)—S—(C₁-C₃)—Ar²wherein Ar, Ar¹ and Ar² are each independently a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated five or sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;said Ar, Ar¹ and Ar² moieties optionally substituted, on one ring if themoiety is monocyclic, or one or both rings if the moiety is bicyclic, oncarbon, nitrogen or sulfur with up to three substituents independentlyselected from R¹, R² and R³ wherein R¹, R² and R³ are oxo, H, hydroxy,nitro, halo, (C₁-C₆)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxycarbonyl, (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl(C₁-C₄)alkanoyl, formyl,(C₁-C₈)alkanoyl, (C₁-C₆)alkanoyl(C₁-C₆)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfinyl; R¹, R² and R³ are optionally mono-,di- or tri-substituted independently on carbon with halo or hydroxy; andV is a bond or (C₁-C₃)alkylene optionally mono-unsaturated andoptionally mono- or di-substituted independently with hydroxy or fluorowith the proviso that when K is (C₂-C₄)alkylene and M is Ar and Ar iscyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said(C₅-C₈)cycloalkyl substituents are not substituted at the one positionwith hydroxy and with the proviso that6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and itsethyl ester are not included.
 136. A pharmaceutical compositioncomprising: a. a therapeutically effective amount of a compound of claim135 or a pharmaceutically acceptable salt or prodrug thereof; b. atherapeutically effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olor a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharmaceutically acceptable salt thereof and c. a pharmaceuticalcarrier.
 137. A method for treating a mammal having a condition whichpresents with low bone mass comprising administering to said mammal a. atherapeutically effective amount of a compound of claim 135 or apharmaceutically acceptable salt or prodrug thereof; and b. atherapeutically effective amount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olor a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or pharmaceuticallyacceptable salt thereof.
 138. A kit comprising: a. a therapeuticallyeffective amount of a compound of claim 135 or a pharmaceuticallyacceptable salt or prodrug thereof and a pharmaceutically acceptablecarrier in a first unit dosage form; b. a therapeutically effectiveamount of2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olor a pharmaceutically acceptable salt thereof or3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or apharamceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier in a second unit dosage form; and c. container meansfor containing said first and second dosage forms.
 139. A method fortreating a mammal in need of kidney regeneration comprisingadministering to said mammal a therapeutically effective amount of acompound of claim 135 or a pharmaceutically acceptable salt or prodrugthereof.
 140. A method for treating a mammal having a condition whichpresents with low bone mass comprising administering to said mammal atherapeutically effective amount of a compound of claim 135 or apharmaceutically acceptable salt or prodrug thereof.
 141. Apharmaceutical composition which comprises a therapeutically effectiveamount of a compound of claim 135 or a pharmaceutically acceptable saltor prodrug thereof and a pharmaceutically acceptable carrier.